Crystalline methyl (4R,12aS)-7-(benzyloxy)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylate

ABSTRACT

A crystalline methyl (4R,12aS)-7-(benzyloxy)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5] pyrazino[2,1-b][1,3]oxazine-9-carboxylate of the formula (U2):

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application is a divisional application of U.S. Ser. No. 15/072,388filed on Mar. 17, 2016 which is a divisional application of U.S. Ser.No. 14/518,209 filed on Oct. 20, 2014, which is a divisional applicationof U.S. Ser. No. 13/814,333 filed on May 16, 2013, now abandoned, whichwas filed pursuant to 35 USC 371 as a United States National PhaseApplication of International Patent Application Serial No.PCT/JP2011/067832 filed on Aug. 4, 2011, which claims priority from2010-175899 filed on Aug. 5, 2010 and 2010-277713 filed on Dec. 14, 2010in Japan.

TECHNICAL FIELD

The present invention relates to a method of producing compounds havingHIV integrase inhibitory activity, using a novel method of producingpyrone derivatives and pyridone derivatives.

BACKGROUND ART

Patent Document 1 describes compounds (I) and (II), which are useful asanti-HIV drugs and shown by formulae:

This document describes the following reaction formula as a method ofproducing compound (I).

Furthermore, Patent Documents 2 to 6 describe the following reactionformula as an improved method of producing compound (I).

However, the above production methods of these documents are notsatisfactory for the industrial manufacturing method because of thefollowings:

these reaction processes for obtaining compound (I) include 16 or 11steps, respectively, and are very long,

the total yield is low, thus being inefficient,

a high toxic and harmful reaction is used.

an expensive reagent is used,

an environmentally harmful reagent is used.

Therefore, the development of a method for more efficient industrialmass-production of compound (I), compound (II) and their derivatives hasbeen desired.

Non-Patent Documents 1 and 2 describe a method of producing pyrane-4-oneand pyridine 4-one. Patent Document 7 and Non-Patent Document 3 describea method of producing enaminone derivatives. However, a method ofproducing pyronediester and pyridonediester of the present invention isnot described in these documents. Furthermore, a method of manufacturingcompounds having HIV-integrase inhibitory activity by using theproduction method of the present invention is not disclosed. PatentDocument 8 is an international patent application by the presentapplicant. Though this document describes the method of producingpyronediester and pyridonediester identical to the present invention,compounds having HIV-integrase inhibitory activity and anti-HIV drugsare not described therein.

PRIOR ART DOCUMENTS Patent Documents

-   [Patent Document 1] International publication No. 2006/116764    pamphlet-   [Patent Document 2] International publication No. 2010/011812    pamphlet-   [Patent Document 3] International publication No. 2010/011819    pamphlet-   [Patent Document 4] International publication No. 2010/068262    pamphlet-   [Patent Document 5] International publication No. 2010/067176    pamphlet-   [Patent Document 6] International publication No. 2010/068253    pamphlet-   [Patent Document 7] U.S. Pat. No. 4,769,380A-   [Patent Document 8] International application PCT/JP2010/055316

Non-Patent Documents

-   [Non-Patent Document 1] Journal of Organic Chemistry, 1991, 56(16),    4963-4967-   [Non-Patent Document 2] Science of Synthesis, 2005, 15, 285-387-   [Non-Patent Document 3] Journal of Chemical Society Parkin    Transaction. 1, 1997, Issue. 2, 163-169

SUMMARY OF THE INVENTION Problem to be Solved by the Invention

An object of the present invention is to efficiently produce compoundsuseful as an anti-HIV drug having HIV-integrase inhibitory activity,which are shown by formula (Y1) or formula (Y2), a pharmaceuticallyacceptable salt thereof, or their solvate, by using a novel pyronederivative and a pyridone derivative, a method of producing the same,and a method of using the same:

(wherein R^(x) is carbocyclyl optionally substituted by substituent E,heterocyclyl optionally substituted by substituent E, carbocyclyl loweralkyl optionally substituted by substituent E, or heterocyclyl loweralkyl optionally substituted by substituent E.Substituent E: halogen, cyano, hydroxy, carboxy, formyl, amino, oxo,nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy, carbocyclyloptionally substituted by substituent F, heterocyclyl optionallysubstituted by substituent F, carbocyclyl lower alkyloxy optionallysubstituted by substituent F, heterocyclyl lower alkyloxy optionallysubstituted by substituent F, carbocyclyl lower alkylthio optionallysubstituted by substituent F, heterocyclyl lower alkylthio optionallysubstituted by substituent F, carbocyclyl lower alkylamino optionallysubstituted by substituent F, heterocyclyl lower alkylamino optionallysubstituted by substituent F, carbocyclyloxy optionally substituted bysubstituent F, heterocyclyloxy optionally substituted by substituent F,carbocyclylcarbonyl optionally substituted by substituent F,heterocyclylcarbonyl optionally substituted by substituent F,carbocyclylaminocarbonyl optionally substituted by substituent F,heterocyclylaminocarbonyl optionally substituted by substituent F,halogeno lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxylower alkyloxy, lower alkylcarbonyl, lower alkyloxycarbonyl, loweralkyloxycarbonylamino, lower alkylamino, lower alkylcarbonylamino, loweralkylaminocarbonyl, lower alkylsulfonyl, and lower alkylsulfonylamino;Substituent F: halogen, hydroxy, carboxy, amino, oxo, nitro, loweralkyl, halogeno lower alkyl, lower alkyloxy, and amino protective group)

Means for Solving the Problems

The prevent invention provides the following items, which relate to aproduction method shown by the following reaction formula:

(Item 1)

A method of producing a compound shown by formula (Y1) or formula (Y2)or a salt thereof:

(wherein R^(x) is carbocyclyl optionally substituted by substituent E,heterocyclyl optionally substituted by substituent E, carbocyclyl loweralkyl optionally substituted by substituent E, or heterocyclyl loweralkyl optionally substituted by substituent E, and substitutent E is asdefined below) comprising a step of:(Step B)reacting a compound shown by formula (X2):

(wherein,R^(1d) is hydrogen, halogen, lower alkyloxy optionally substituted bysubstituent E, carbocyclyl lower alkyloxy optionally substituted bysubstituent E, heterocyclyl lower alkyloxy optionally substituted bysubstituent E, or —OSi(R^(1e))₃,R^(1e)s are each independently lower alkyl optionally substituted bysubstituent E, carbocyclyl optionally substituted by substituent E,heterocyclyl optionally substituted by substituent E, carbocyclyl loweralkyl optionally substituted by substituent E, or heterocyclyl loweralkyl optionally substituted by substituent E,R^(2d) is hydrogen, lower alkyl optionally substituted by substituent E,carbocyclyl lower alkyl optionally substituted by substituent E, orheterocyclyl lower alkyl optionally substituted by substituent E,R^(3d) is hydrogen, lower alkyloxy optionally substituted by substituentE, —N(R^(3e))₂, or —OR^(3e),R^(3e)s are each independently lower alkyl optionally substituted bysubstituent E, or two R^(3e)s in —N(R^(3e))₂ together with the adjacentnitrogen atom may form a heterocycle, anda wavy line means E form and/or Z form or a mixture thereof.Substituent E: halogen, cyano, hydroxyl, carboxy, formyl, amino, oxo,nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy, carbocyclyloptionally substituted by substituent F, heterocyclyl optionallysubstituted by substituent F, carbocyclyl lower alkyloxy optionallysubstituted by substituent F, heterocyclyl lower alkyloxy optionallysubstituted by substituent F, carbocyclyl lower alkylthio optionallysubstituted by substituent F, heterocyclyl lower alkylthio substitutedby substituent F, carbocyclyl lower alkylamino optionally substituted bysubstituent F, heterocyclyl lower alkylamino optionally substituted bysubstituent F, carbocyclyloxy optionally substituted by substituent F,heterocyclyloxy optionally substituted by substituent F,carbocyclylcarbonyl optionally substituted by substituent F,heterocyclylcarbonyl optionally substituted by substituent F,carbocyclylaminocarbonyl optionally substituted by substituent F,heterocyclylaminocarbonyl optionally substituted by substituent F,halogeno lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxylower alkyloxy, lower alkylcarbonyl, lower alkyloxycarbonyl, loweralkyloxy carbonylamino, lower alkylamino, lower alkylcarbonylamino,lower alkylaminocarbonyl, lower alkylsulfonyl, and loweralkylsulfonylamino;Substituent F: halogeno, hydroxyl, carboxy, amino, oxo, nitro, loweralkyl, halogeno lower alkyl, lower alkyloxy, and amino protecting group)with a compound shown by formula (V2):

(wherein,R^(4d) is lower alkyl optionally substituted by substituent E,carbocyclyl lower alkyl optionally substituted by substituent E, orheterocyclyl lower alkyl optionally substituted by substituent E,R^(5d) is hydrogen, halogen, lower alkyloxy optionally substituted bysubstituent E, or —O—SO₂—R^(5e),R^(5e) is lower alkyl optionally substituted by substituent E,carbocyclyl optionally substituted by substituent E, heterocyclyloptionally substituted by substituent E, carbocyclyl lower alkyloptionally substituted by substituent E, or heterocyclyl lower alkylsubstituted by substituent E, and Substituent E is as defined above)to obtain a compound shown by formula (X3) or a salt thereof:

(wherein each symbol is as defined above).(Item 2)

A method of producing a compound shown by formula (Y1) or formula (Y2),or a salt thereof:

(wherein R^(x) is as defined in Item 1)comprising a step of:(Step C)reacting a compound shown by formula (X3), or a salt thereof:

(wherein each symbol is as defined above).with a compound shown by formula (V3), or a salt thereof:[Chemical formula 12]H₂N—R^(6d)  (V3)(wherein R^(6d) is lower alkyl optionally substituted by substituent E,or lower alkenyl optionally substituted by substituent E, andsubstituent E is as defined in Item 1).to obtain a compound shown by formula (X4), or a salt thereof:

(wherein each symbol is as defined in Item 1 or above).(Item 3)

A method of producing of a compound shown by formula (Y1) or formula(Y2), or a salt thereof:

(wherein each symbol is as defined in Item 1)comprising a step of:(Step D)reacting a compound shown by formula (X4), or a salt thereof:

(wherein each symbol is as defined in Item 1 or Item 2) with(R)-3-amino-butan-1-ol, or (5)-2-amino-propan-1-ol to obtain a compoundshown by formula (X5) or formula (X5′):

(wherein each symbol is as defined in Item 1).(Item 4)

A method according to Item 1 comprising a step of:

(Step C)

reacting a compound shown by formula (X3), or a salt thereof:

(wherein each symbol is as defined in Item 1)with a compound shown by formula (V3), or a salt thereof:[Chemical formula 18]H₂N—R^(6d)  (V3)(wherein R^(6d) is as defined in Item 2)to obtain a compound shown by formula (X4), or a salt thereof:

(wherein each symbol is as defined in Item 1 or Item 2).(Item 5)

A method according to Item 4 comprising a step of:

(Step D)

reacting a compound shown by formula (X4), or a salt thereof:

(wherein each symbol is as defined in Item 1 or Item 2)with (R)-3-amino-butan-1-ol, or (S)-2-amino-propan-1-ol to obtain acompound shown by formula (X5) or formula (X5′), or a salt thereof:

(wherein each symbol is as defined in Item 1).(Item 6)

A method according to Item 3 or 5 comprising a step of:

(Step E)

reacting a compound shown by formula (X5) or formula (X5′), or a saltthereof:

(wherein each symbol is as defined in Item 1)with a compound shown by formula (V6), or a salt thereof:[Chemical formula 23]R^(X)—NH₂  (V6)(wherein R^(x) is as defined in Item 1)to obtain a compound shown by formula (X6) or formula (X6′), or a saltthereof:

(wherein each symbol is as defined in Item 1).(Item 7)

A method according to Item 4, 5 or 6, wherein Step B and Step C arecontinuously performed.

(Item 8)

A method of producing of a compound shown by formula (Y1) or formula(Y2), or a salt thereof:

(wherein R^(x) is as defined in Item 1)comprising a step of:(Step B′)reacting a compound shown by formula (X2):

(wherein each symbol is as defined in Item 1)with a compound shown by formula (V2):

(wherein each symbol is as defined in Item 1)and a compound shown by formula (V2′):[Chemical formula 28]NH⁴⁺X^(d−)  (V2′)(wherein X^(d−) is a counter anion of ammonium cation)to obtain a compound shown by formula (X4′), or a salt thereof:

(wherein each symbol is as defined in Item 1).(Item 9)

A method according to Item 8 comprising a step of:

(Step C′)

reacting a compound shown by formula (X4′):

(wherein each symbol is as defined in Item 1)with a compound shown by formula (V3′):[Chemical formula 31]R^(6d)-L^(d)  (V3′)(wherein R^(6d) is as defined in Item 2, L^(d) is a leaving group)to obtain a compound shown by formula (X4), or a salt thereof:

(wherein each symbol is as defined in Item 1 or 2).(Item 10)

A method according to Item 9 comprising a step of:

(Step D)

reacting a compound shown by formula (X4):

(wherein each symbol is as defined in Item 1 or Item 2)with (R)-3-amino-butan-1-ol or (5)-2-amino-propan-1-ol to obtain acompound shown by formula (X5) or formula (X5′), or a salt thereof:

(wherein each symbol is as defined in Item 1).(Item 11)

A method according to Item 10 comprising a step of:

(Step E)

reacting a compound shown by formula (X5) or formula (X5′):

(wherein each symbol is as defined in Item 1)with a compound shown by formula (V6), or a salt thereof:[Chemical formula 36]R^(X)—NH₂  (V6)(wherein R^(x) is as defined in Item 1)to obtain a compound shown by formula (X6) or formula (X6′), or a saltthereof:

(wherein each symbol is as defined in Item 1).(Item 12)

A method according to Item 1, or any one of Items 4 to 11, wherein thecompound shown by formula (X2) is obtained by reacting a compound shownby formula (X1):

(wherein each symbol is as defined in Item 1)with a compound shown by formula (V1):

(wherein P^(d) is lower alkyl optionally substituted by substituent E,and R^(3d) and substituent E are as defined in Item 1).(Item 13)

A method according to Item 1 or any one of Items 4 to 11, wherein thecompound shown by formula (X2) is obtained by reacting a compound shownby formula (Z1):

(wherein each symbol is as defined in Item 1)with a compound shown by formula (Z2):

(wherein each symbol is as defined in Item 1).(Item 14)

A method according to any one of Items 1 to 13, wherein R^(x) iscarbocyclyl lower alkyl optionally substituted by substituent E.

(Item 15)

A method according to any one of Items 1 to 13, wherein R^(x) is2,4-difluorobenzyl.

(Item 16)

A method of producing a compound shown by formula (Y1) or formula (Y2),or a salt thereof:

(wherein R^(x) is as defined in Item 1)comprising steps of:(Step C″)reacting a compound shown by formula (W1):

with a compound shown by formula (V3), or a salt thereof:[Chemical formula 44]H₂N—R^(6d)  (V3)(wherein R^(6d) is as defined in Item 2)to obtain a compound shown by formula (W2), or a salt thereof:

(wherein R^(6d) is as defined in Item 2), and(Step D″)reacting a compound shown by formula (W2) with (R)-3-amino-burane-1-olor (5)-2-amino-propan-1-ol to obtain a compound shown by formula (W3) orformula (W4), or a salt thereof:

and(Step F)reacting a compound shown by formula (W3) or formula (W4) with ahalogenating agent to obtain a compound shown by formula (W5) or formula(W6), or a salt thereof:

(wherein Hal is a halogen atom).(Item 17)

A crystal of a compound shown by formula (U1) or a solvate thereof:

(wherein Me is methyl, and Bn is benzyl)which has peaks in a powder X-ray diffraction spectrum at diffractionangle (2θ): 11.2°±0.2°, 17.2°±0.2°, 17.7°±0.2°, 20.5°±0.2°, 22.0°±0.2°and 26.1°±0.2°.(Item 18)

A crystal of a compound shown by formula (U2) or a solvate thereof:

(wherein Me is methyl, and Bn is benzyl)which has peaks in a powder X-ray diffraction spectrum at diffractionangle (2θ): 7.3°±0.2°, 14.4°±0.2°, 16.1°±0.2°, 18.4°±0.2°, 22.3°±0.2°and 23.1°±0.2°.(Item 19)

A crystal of a compound shown by formula (U3) or a solvate thereof:

(wherein Me is methyl, and Bn is benzyl)which has peaks in a powder X-ray diffraction spectrum at diffractionangle (2θ): 7.2°±0.2°, 16.1°±0.2°, 18.3°±0.2°, 20.6°±0.2°, 22.6°±0.2°,23.1°±0.2° and 23.7°±0.2°.(Item 20)

A crystal according to Item 17, which is characterized by a powder X-raydiffraction spectrum substantially consistent with FIG. 1.

(Item 21)

A crystal according to Item 18, which is characterized by a powder X-raydiffraction spectrum substantially consistent with FIG. 2.

(Item 22)

A crystal according to Item 19, which is characterized by a powder X-raydiffraction spectrum substantially consistent with FIG. 3.

The present invention provides the following items as other embodiments.

(Item I)

A method of producing a compound shown by formula (Y1) or formula (Y2)or a salt thereof:

(wherein R^(x) is carbocyclyl optionally substituted by substituent E,heterocyclyl optionally substituted by substituent E, carbocyclyl loweralkyl optionally substituted by substituent E, or heterocyclyl loweralkyl substituted by substituent E, and substituent E is as definedbelow)comprising a step of reacting a compound shown by formula (X2):

(wherein R^(1d) is hydrogen, halogen, lower alkyloxy optionallysubstituted by substituent E, carbocyclyl lower alkyloxy optionallysubstituted by substituent E, heterocyclyl lower alkyloxy optionallysubstituted by substituent E, or —OSi(R^(1e))₃,R^(1e)s are each independently lower alkyl optionally substituted bysubstituent E, carbocyclyl optionally substituted by substituent E,heterocyclyl optionally substituted by substituent E, carbocyclyl loweralkyl optionally substituted by substituent E, or heterocyclyl loweralkyl substituted by substituent E,R^(2d) is hydrogen, lower alkyl optionally substituted by substituent E,carbocyclyl optionally substituted by substituent E, or heterocyclyllower alkyl optionally substituted by substituent E,R^(3d) is hydrogen, lower alkyloxy optionally substituted by substituentE, —N(R^(3e))₂, or —OR^(3e),R^(3e)s are each independently lower alkyl optionally substituted bysubstituent E, or two R^(3e)s in —N(R^(3e))₂ together with the adjacentnitrogen atom may form a heterocycle, andthe wavy line means E form and/or Z form or their mixture.Substituent E: halogen, cyano, hydroxy, carboxy, formyl, amino, oxo,nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy, carbocyclyloptionally substituted by substituent F, heterocyclyl optionallysubstituted by substituent F, carbocyclyl lower alkyloxy optionallysubstituted by substituent F, heterocyclyl lower alkyloxy optionallysubstituted by substituent F, carbocyclyl lower alkylthio optionallysubstituted by substituent F, heterocyclyl lower alkylthio substitutedby substituent F, carbocyclyl lower alkylamino optionally substituted bysubstituent F, heterocyclyl lower alkylamino optionally substituted bysubstituent F, carbocyclyloxy optionally substituted by substituent F,heterocyclyloxy optionally substituted by substituent F,carbocyclylcarbonyl optionally substituted by substituent F,heterocyclylcarbonyl optionally substituted by substituent F,carbocyclcylaminocarbonyl optionally substituted by substituent F,heterocyclylaminocarbonyl optionally substituted by substituent F,halogeno lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxylower alkyloxy, lower alkylcarbonyl, lower alkyloxycarbonyl, loweralkyloxycarbonylamino, lower alkylamino, lower alkylcarbonylamino, loweralkylaminocarbonyl, lower alkylsulfonyl, and lower alkylsulfonylamino;Substituent F: halogen, hydroxyl, carboxy, amino, oxo, nitro, loweralkyl, halogeno lower alkyl, lower alkyloxy, and amino protective group)with a compound shown by formula (V2):

(wherein R^(4d) is lower alkyl optionally substituted by substituent E,carbocyclyl lower alkyl optionally substituted by substituent E, orheterocyclyl lower alkyl substituted by substituent E,R^(5d) is hydrogen, halogen, lower alkyloxy substituted by substituentE, or —O—SO²—R^(5e),R^(5e) is lower alkyl optionally substituted by substituent E,carbocyclyl optionally substituted by substituent E, heterocyclyloptionally substituted by substituent E, carbocyclyl lower alkyloptionally substituted by substituent E, or heterocyclyl lower alkyloptionally substituted by substituent E, and substituent E is as definedabove)to obtain a compound shown by formula (X3) or a salt thereof:

(wherein each symbol is as defined above).(Item II)

A method of producing a compound shown by formula (Y1) or formula (Y2)or a salt thereof:

(wherein R^(x) is as defined in Item I)comprising a step of reacting a compound shown by formula (X3) or a saltthereof:

(wherein each symbol is as defined in Item I)with a compound shown by formula (V3), or a salt thereof:[Chemical formula 57]H₂N—R^(6d)  (V3)(wherein R^(6d) is lower alkyl optionally substituted by substituent E,or lower alkenyl optionally substituted by substituent E, andsubstituent E is as defined in Item I)to obtain a compound shown by formula (X4), or a salt thereof:

(wherein each symbol is as defined in Item I or above).(Item III)

A method of producing a compound shown by formula (Y1) or formula (Y2),or a salt thereof:

(wherein R^(x) is as defined in Item I)comprising a step of reacting a compound shown by formula (X4), or asalt thereof:

(wherein each symbol is as defined in Item I or II)with (R)-3-amino-butan-1-ol or (5)-2-amino-propan-1-ol to obtain acompound shown by formula (X5) or formula (X5′):

(wherein each symbol is as defined in Item I).(Item IV)

A method of producing a compound shown by formula (Y1) or formula (Y2),or a salt thereof:

(wherein R^(x) is as defined in Item I)comprising steps of:(Step B)reacting a compound shown by formula (X2):

(wherein each symbol is as defined in Item I)with a compound shown by formula (V2):

(wherein each symbol is as defined in Item I)to obtain a compound shown by formula (X3) or a salt thereof:

(wherein each symbol is as defined in Item I); and(Step C)reacting a compound shown by formula (X3) or a salt thereof with acompound shown by formula (V3), or a salt thereof:[Chemical formula 66]H₂N—R^(6d)  (V3)(wherein R^(6d) is as defined in Item II)to obtain a compound shown by formula (X4), or a salt thereof:

(wherein each symbol is as defined in Item I or II).(Item IV′)

A method of producing a compound shown by formula (Y1) or formula (Y2),or a salt thereof:

(wherein R^(x) is as defined in Item I)comprising steps of:(Step B)reacting a compound shown by formula (X2):

(wherein each symbol is as defined in Item I)with a compound shown by formula (V2):

(wherein each symbol is as defined in Item I)to obtain a compound shown by formula (X3), or a salt thereof:

(wherein each symbol is as defined in Item I);(Step C)reacting a compound shown by formula (X3) with a compound shown byformula (V3), or a salt thereof:[Chemical formula 72]H₂N—R^(6d)  (V3)(wherein R^(6d) is as defined in Item II)to obtain a compound shown by formula (X4), or a salt thereof:

(wherein each symbol is as defined in Item I or II); and(Step D)reacting a compound shown by formula (X4), or a salt thereof with(R)-3-amino-butan-1-ol or (S)-2-amino-propan-1-ol to obtain a compoundshown by formula (X5) or formula (X5′), or a salt thereof:

(wherein each symbol is as defined in Item I).(Item IV″)

A method of producing a compound shown by formula (Y1) or formula (Y2),or a salt thereof:

(wherein R^(x) is as defined in Item I)comprising steps of:(Step B)reacting a compound shown by formula (X2):

(wherein each symbol is as defined in Item I)with a compound shown by formula (V2):

(wherein each symbol is as defined in Item I)to obtain a compound shown by formula (X3), or a salt thereof:

(wherein each symbol is as defined in Item I); and(Step C)reacting a compound shown by formula (X3) with a compound shown byformula (V3), or a salt thereof:[Chemical formula 79]H₂N—R^(6d)  (V3)(wherein R^(6d) is as defined in Item II)to obtain a compound shown by formula (X4), or a salt thereof:

(wherein each symbol is as defined in Item I or II);(Step D)reacting a compound shown by formula (X4), or a salt thereof with(R)-3-amino-butan-1-ol or (S)-2-amino-propan-1-ol to obtain a compoundshown by formula (X5) or formula (X5′), or a salt thereof:

(wherein each symbol is as defined in Item I); and(Step E)reacting with a compound shown by formula (V6), or a salt thereof:[Chemical formula 82]R^(X)—NH₂  (V6)(wherein R^(x) is as defined in Item I).(Item V)

A method according to Item IV, IV′, or IV″, wherein Step B and Step Care continuously performed.

(Item VI)

A method of producing a compound shown by formula (Y1) or formula (Y2),or a salt thereof:

(wherein R^(x) is as defined in Item I)comprising a step of reacting a compound shown by formula (X2):

(wherein each symbol is as defined in Item I)with a compound shown by formula (V2):

(wherein each symbol is as defined in Item I)and a compound shown by formula (V2′)[Chemical formula 86]NH⁴⁺X^(d−)  (V2′)(wherein X^(d−) is a counter anion of ammonium cation)to obtain a compound shown by formula (X4′), or a salt thereof:

(wherein each symbol is as defined in Item I).(Item VII)

A method of producing a compound shown by formula (Y1) or formula (Y2),or a salt thereof:

(wherein R^(x) is as defined in Item I)comprising steps of:(Step B′)reacting a compound shown by formula (X2):

(wherein each symbol is as defined in Item I)with a compound shown by formula (V2):

(wherein each symbol is as defined in Item I)and a compound shown by formula (V2′):[Chemical formula 91]NH⁴⁺X^(d−)  (V2′)(wherein X^(d−) is a counter anion of ammonium cation)to obtain a compound shown by formula (X4′), or a salt thereof:

(wherein each symbol is as defined in Item I); and(Step C′)reacting a compound shown by formula (X4′) with a compound shown byformula (V3′):[Chemical formula 93]R^(6d)-L^(d)  (V3′)(wherein R^(6d) is as defined in Item II, and L^(d) is a leaving group)to obtain a compound shown by formula (X4), or a salt thereof:

(wherein each symbol is as defined in Item I or II).(Item VII′)

A method of producing a compound shown by formula (Y1) or formula (Y2),or a salt thereof:

(wherein R^(x) is as defined in Item I)comprising steps of:(Step B′)reacting a compound shown by formula (X2):

(wherein each symbol is as defined in Item I)with a compound shown by formula (V2):

(wherein each symbol is as defined in Item I)and a compound shown by formula (V2′):[Chemical formula 98]NH⁴⁺X^(d−)  (V2′)(wherein X^(d−) is a counter anion of ammonium cation)to obtain a compound shown by formula (X4′), or a salt thereof:

(wherein each symbol is as defined in Item I);(Item C′)reacting a compound shown by formula (X4′) with a compound shown byformula (V3′):[Chemical formula 100]R^(6d)-L^(d)  (V3′)(wherein R^(6d) is as defined in Item II, and L^(d) is a leaving group)to obtain a compound shown by formula (X4), or a salt thereof:

(wherein each symbol is as defined in Item I or II); and(Step D)reacting a compound shown by formula (X4) with (R)-3-amino-butan-1-ol or(5)-2-amino-propan-1-ol to obtain a compound shown by formula (X5) orformula (X5′), or a salt thereof:

(wherein each symbol is as defined in Item I).(Item VII″)

A method of producing a compound shown by formula (Y1) or formula (Y2),or a salt thereof:

(wherein R^(x) is as defined in Item I)comprising steps of:(Step B′)reacting a compound shown by formula (X2):

(wherein each symbol is as defined in Item I)with a compound shown by formula (V2):

(wherein each symbol is as defined in Item I)and a compound shown by formula (V2′):[Chemical formula 106]NH⁴⁺X^(d−)  (V2′)(wherein X^(d−) is a counter anion of ammonium cation)to obtain a compound shown by formula (X4′), or a salt thereof:

(wherein each symbol is as defined in Item I);(Step C′)reacting a compound shown by formula (X4′) or a salt thereof with acompound shown by formula (V3′):[Chemical formula 108]R^(6d)-L^(d)  (V3′)(wherein R^(6d) is as defined in Item II and L^(d) is a leaving group)to obtain a compound shown by formula (X4), or a salt thereof:

(wherein each symbol is as defined in Item I or II);(Step D)reacting a compound shown by formula (X4) with (R)-3-amino-butan-1-ol or(5)-2-amino-propan-1-ol to obtain a compound shown by formula (X5) orformula (X5′), or a salt thereof:

(wherein each symbol is as defined in Item I); and(Step E)reacting with a compound shown by formula (V6), or a salt thereof:[Chemical formula 111]R^(X)—NH₂  (V6)(wherein R^(x) is as defined in Item I).(Item VIII)

A method according to any one of Items I, IV, IV′, IV″, VI, VII, VII′,or VII″, wherein A compound shown by formula (X2) is obtained byreacting a compound shown by formula (X1):

(wherein each symbol is as defined in Item I)with a compound shown by formula (V1):

(wherein P^(d) is lower alkyl optionally substituted by substituent E,and R^(3d) and substituent E are as defined in Item I).(Item IX)

A method according to any one of Items I, IV, IV′, IV″, VI, VII, VII′,or VII″, wherein a compound shown by formula (X2) is obtained byreacting a compound by formula (Z1):

(wherein each symbol is as defined in Item I)with a compound shown by formula (Z2):

(wherein each symbol is as defined in Item I).(Item X)

A method according to any one of Items I to VII, IV′, IV″, VII′, andVII″, wherein R^(x) is carbocyclyl lower alkyl optionally substituted bysubstituent E.

(Item XI)

A method according to any one of Item I to VII, IV′, IV″, VII′, andVII″, wherein R^(x) is 2,4-difluorobenzyl.

Effect of the Invention

The present invention enables production of compound (Y1) and compound(Y2) useful as anti-HIV drugs having HIV integrase inhibitory activityin a short step as compared to conventional methods, so the compoundscan be efficiently produced in a high yield. In addition, the presentinvention has a number of advantages, that use of a reaction reagentwith toxicity can be avoided, use of harmful reaction can be avoided,use of an expensive reaction reagent can be avoided, use of anenvironmentally harmful reagent and solvent can be avoided, and thelike. Therefore, the present invention is useful for the industrialproduction of anti-HIV drugs.

In addition, the crystals of compound (U1), compound (U2), and compound(U3) according to the present invention have advantages such as highstability to heat, high stability to light, high purification effect toremove impurities, easy handling, and/or small hygroscopy, andtherefore, can be efficiently produced by utilizing those advantages.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a powder X-ray diffraction pattern of compound 12B obtained inStep 1 of Example 12. The ordinate represents peak intensity, and theabscissa represents a diffraction angle (2θ).

FIG. 2 is a powder X-ray diffraction pattern of compound 15A obtained inExample 15A. The ordinate represents peak intensity, and the abscissarepresents a diffraction angle (2θ).

FIG. 3 is a powder X-ray diffraction pattern of compound 15B obtained inExample 15B. The ordinate represents peak intensity, and the abscissarepresents a diffraction angle (2θ).

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the terms described in the present specification will bedescribed. Each term alone or in combination with other terms has thesame meaning.

The term “halogen” encompasses fluorine, chlorine, bromine, and iodineatoms.

The term “lower alkyl” encompasses linear or branched alkyl having 1 to15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6carbon atoms, further preferably 1 to 4 carbon atoms, most preferably 1or 2 carbon atoms. Examples thereof include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl,isooctyl, n-nonyl, and n-decyl. Examples of preferred embodiments of“lower alkyl” include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, and n-pentyl. Examples of morepreferred embodiments thereof include methyl, ethyl, n-propyl,isopropyl, and tert-butyl.

The term “lower alkenyl” encompasses linear or branched alkenyl having 2to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2to 6 carbon atoms, further preferably 2 to 4 carbon atoms and having oneor more double bonds at an arbitrary position. Specifically, the “loweralkenyl” encompasses vinyl, allyl, propenyl, isopropenyl, butenyl,isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl,hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl,undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, and thelike. Examples of preferred embodiments of “lower alkenyl” includevinyl, allyl, propenyl, isopropenyl, and butenyl. Examples ofparticularly preferred embodiments thereof include allyl.

The lower alkyl moieties of “lower alkyloxy”, “lower alkylcarbonyl”,“lower alkyloxycarbonyl”, “carbocyclyl lower alkyl”, “heterocyclyl loweralkyl”, “halogeno lower alkyl”, “carbocyclyl lower alkyloxy”,“heterocyclyl lower alkyloxy”, “halogeno lower alkyloxy”, “loweralkyloxy lower alkyl”, “lower alkyloxy lower alkyloxy”, “loweralkylamino”, “lower alkylcarbonylamino”, “lower alkylaminocarbonyl”,“lower alkylsulfonyl”, “lower alkylsulfonylamino”, “carbocyclyl loweralkylthio”, “heterocyclyl lower alkylthio”, “carbocyclyl loweralkylamino”, and “heterocyclyl lower alkylamino” are also the same asthe “lower alkyl” described above.

The halogen moieties of “halogeno lower alkyl” and “halogeno loweralkyloxy” are also the same as the “halogen” described above. In thiscontext, the “lower alkyl” and the “lower alkyloxy” may be substitutedby one halogen atom or more identical or different halogen atoms attheir respective arbitrary positions on the alkyl groups.

The term “carbocyclyl” means carbocyclyl having 3 to 20 carbon atoms,preferably 3 to 16 carbon atoms, more preferably 4 to 12 carbon atomsand encompasses cycloalkyl, cycloalkenyl, aryl, non-aromatic condensedcarbocyclyl, and the like.

The “cycloalkyl” means carbocyclyl having 3 to 16 carbon atoms,preferably 3 to 12 carbon atoms, more preferably 4 to 8 carbon atoms andencompasses, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

The “cycloalkenyl” encompasses a group having one or more double bondsat an arbitrary position in the ring of the cycloalkyl. Examples thereofinclude cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptynyl, cyclooctynyl, and cyclohexadienyl.

The “aryl” encompasses phenyl, naphthyl, anthryl, phenanthryl, and thelike. Particularly, phenyl is preferred.

The “non-aromatic condensed carbocyclyl” encompasses a group in whichtwo or more cyclic groups selected from the “cycloalkyl”,“cycloalkenyl”, and “aryl” described above are condensed. Examplesthereof include indanyl, indenyl, tetrahydronaphthyl, fluorenyl, andadamantyl.

Examples of preferred embodiments of “carbocyclyl” include cycloalkyl,aryl, and non-aromatic condensed carbocyclyl. Specific examples thereofinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and phenyl.

The carbocyclyl moieties of “carbocyclyl lower alkyl”, “carbocyclyllower alkyloxy”, “carbocyclyl lower alkylthio”, “carbocyclyl loweralkylamino”, “carbocyclyloxy”, “carbocyclylcarbonyl”, and“carbocyclylaminocarbonyl” are also the same as the “carbocyclyl”described above. In this context, the “carbocyclyl lower alkyl” inparticularly preferred embodiments is benzyl.

Examples of preferred embodiments of “carbocyclyl lower alkyloxy”include benzyloxy.

Examples of preferred embodiments of “carbocyclyl lower alkylthio”include benzylthio.

Examples of preferred embodiments of “carbocyclyl lower alkylamino”include benzylamino

Examples of preferred embodiments of “carbocyclyloxy” include phenyloxy.

Examples of preferred embodiments of “carbocyclylcarbonyl” includephenylcarbonyl.

Examples of preferred embodiments of “carbocyclylaminocarbonyl” includephenylaminocarbonyl.

The term “heterocyclyl” encompasses heterocyclyl having, in the ring,one or more identical or different heteroatoms arbitrarily selected fromO, S, and N, such as heteroaryl, none-aromatic heterocyclyl, bicycliccondensed heterocyclyl, and tricyclic condensed heterocyclyl.

Examples of the “heteroaryl” include 5- to 6-membered aromatic cyclylsuch as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl,thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, andthiadiazolyl.

Examples of the “none-aromatic heterocyclyl” include dioxanyl,thiiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl,thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl,pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl,morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl,tetrahydropyridyl, tetrahydrofuryl, tetrahydropyranyl, dihydrothiazolyl,tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl,hexahydroazepinyl, tetrahydrodiazepinyl, tetrahydropyridazinyl,hexahydropyrimidinyl, and dioxolanyl.

Examples of the “bicyclic condensed heterocyclyl” include indolyl,isoindolyl, indazolyl, indolizinyl, indolinyl, isoindolinyl, quinolyl,isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl,quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl,benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl,benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl,isobenzofuryl, benzothienyl, benzotriazolyl, thienopyridyl,thienopyrrolyl, thienopyrazolyl, thienopyrazinyl, furopyrrolyl,thienothienyl, imidazopyridyl, pyrazolopyridyl, thiazolopyridyl,pyrazolopyrimidinyl, pyrazolotriazinyl, pyridazolopyridyl,triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl,quinolyl, isoquinolyl, naphthyridinyl, dihydrothiazolopyrimidinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzofuryl,dihydrobenzoxazinyl, dihydrobenzimidazolyl, tetrahydrobenzothienyl,tetrahydrobenzofuryl, benzodioxolyl, benzodioxonyl, chromanyl,chromenyl, octahydrochromenyl, dihydrobenzodioxynyl,dihydrobenzooxedinyl, dihydrobenzodioxepinyl, and dihydrothienodioxynyl.

Examples of the “tricyclic condensed heterocyclyl” include carbazolyl,acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,dibenzofuryl, imidazoquinolyl, and tetrahydrocarbazolyl.

Examples of preferred embodiments of “heterocyclyl” include 5- to6-membered heteroaryl or none-aromatic heterocyclyl, and tricycliccondensed heterocyclyl.

The heterocyclyl moieties of “heterocyclyl lower alkyl”, “heterocyclyllower alkyloxy”, “heterocyclyl lower alkylthio”, “heterocyclyl loweralkylamino”, “heterocyclyloxy”, “heterocyclylcarbonyl”, and“heterocyclylaminocarbonyl” are also the same as the “heterocyclyl”described above. In this context, the “heterocyclyl lower alkyl” inparticularly preferred embodiments is pyridylmethyl.

Examples of preferred embodiments of “heterocyclyl lower alkyloxy”include pyridylmethyloxy.

Examples of preferred embodiments of “heterocyclyl lower alkylthio”include pyridylmethylthio.

Examples of preferred embodiments of “heterocyclyl lower alkylamino”include pyridylmethylamino.

Examples of preferred embodiments of “heterocyclyloxy” includepyridyloxy.

Examples of preferred embodiments of “heterocyclylcarbonyl” includepyridylcarbonyl.

Examples of preferred embodiments of “heterocyclylaminocarbonyl” includepyridylaminocarbonyl.

The phrase “Step B and Step C are continuously performed” means thatafter the completion of Step B, Step C is carried out without performingthe isolation operation (e.g., crystallization and collection byfiltration, and distillation), extraction operation, and columnchromatography purification of the product of Step B. Step B and Step Cmay be performed in the same or different reactors.

The term “lower alkyl optionally substituted by substituent E” meansthat “lower alkyl” is unsubstituted or is bonded to one or morechemically acceptable substituents selected from substituent E. When thelower alkyl is bonded to a plurality of substituents, these substituentsmay be the same as or different from each other. Examples thereofinclude methyl, fluoromethyl, trifluoromethyl, chlorodifluoromethyl, and

The term “carbocyclyl optionally substituted by substituent E” meansthat “carbocyclyl” is unsubstituted or is bonded to one or morechemically acceptable substituents selected from substituent E. When thecarbocyclyl is bonded to a plurality of substituents, these substituentsmay be the same as or different from each other. The “carbocyclyloptionally substituted by substituent E” encompasses, for example,fluorophenyl, difluorophenyl, and methoxyfluorophenyl.

The term “carbocyclyl lower alkyl optionally substituted by substituentE” means that “carbocyclyl” and/or “lower alkyl” is unsubstituted or isbonded to one or more chemically acceptable substituents selected fromsubstituent E. When the carbocyclyl and/or the lower alkyl is bonded toa plurality of substituents, these substituents may be the same as ordifferent from each other. The “carbocyclyl lower alkyl optionallysubstituted by substituent E” encompasses, for example, 4-fluorobenzyl,2,4-difluorobenzyl, 4-methoxy-2-fluorobenzyl, and4-methoxyphenyldifluoromethyl.

The terms “lower alkyloxy optionally substituted by substituent E”,“carbocyclyl lower alkyloxy optionally substituted by substituent E”,“heterocyclyl lower alkyloxy optionally substituted by substituent E”,and “lower alkenyl optionally substituted by substituent E” are alsodefined similarly.

The term “carbocyclyl optionally substituted by substituent F” meansthat “carbocyclyl” is unsubstituted or is bonded to one or morechemically acceptable substituents selected from substituent F. When thecarbocyclyl is bonded to a plurality of substituents, these substituentsmay be the same as or different from each other. The “carbocyclyloptionally substituted by substituent F” encompasses, for example,fluorophenyl, difluorophenyl, and methoxyfluorophenyl.

The term “carbocyclyl lower alkyloxy optionally substituted bysubstituent F” means that the “carbocyclyl” moiety is unsubstituted oris bonded to one or more chemically acceptable substituents selectedfrom substituent F. When the carbocyclyl moiety is bonded to a pluralityof substituents, these substituents may be the same as or different fromeach other. The “carbocyclyl lower alkyloxy optionally substituted bysubstituent F” encompasses, for example, fluorobenzyloxy,difluorobenzyloxy, and methoxyfluorobenzyloxy.

The terms “heterocyclyl optionally substituted by substituent F”,“heterocyclyl lower alkyloxy optionally substituted by substituent F”,“carbocyclyl lower alkylthio optionally substituted by substituent F”,“heterocyclyl lower alkylthio optionally substituted by substituent F”,“carbocyclyl lower alkylamino optionally substituted by substituent F”,“heterocyclyl lower alkylamino optionally substituted by substituent F”,“carbocyclyloxy optionally substituted by substituent F”,“heterocyclyloxy optionally substituted by substituent F”,“carbocyclylcarbonyl optionally substituted by substituent F”,“heterocyclylcarbonyl optionally substituted by substituent F”,“carbocyclylaminocarbonyl optionally substituted by substituent F”, and“heterocyclylaminocarbonyl optionally substituted by substituent F” arealso defined similarly.

The phrase “two R^(3e)s in —N(R^(3e))₂ together with the adjacentnitrogen atom may form a heterocycle” encompasses, for example, formulasshown below:

The “amino protective group” can be any general protective group for theamino group and exemplified by amino protective groups described in, forexample, Protective Groups in Organic Synthesis, Theodora W Greene (JohnWiley & Sons). The “amino protective group” is preferably atert-butyloxycarbonyl or benzyloxycarbonyl group.

The “carboxyl protective group” can be any general protective group forthe carboxyl group and exemplified by carboxyl protective groupsdescribed in, for example, Protective Groups in Organic Synthesis,Theodora W Greene (John Wiley & Sons). Preferred examples thereofinclude methyl, ethyl, tert-butyl, methoxymethyl, allyl, benzyl, andp-methoxybenzyl groups.

Examples of the “counter anion of ammonium cation” represented by X^(d)include halogen⁻, CH₃COO⁻, HCOO⁻, NO₃ ⁻, BF₄ ⁻, PF₆ ⁻, HO⁻, Ph-SO₃ ⁻,CH₃-Ph-SO₃ ⁻, CH₃—SO₃ ⁻, PO₄ ³⁻, SO₄ ²⁻ and HSO₄ ⁻. The “counter anionof ammonium cation” is preferably halogen⁻, CH₃COO⁻, NO₃ ⁻, or SO₄ ²⁻.In the case of divalent or trivalent anion, the counter anion representsthat each NH₄ ⁺ cation is in an uncharged state by the binding of two orthree molecules thereof. Specific examples of NH₄ ⁺X^(d−) include NH₄⁺Cl⁻, NH₄ ⁺CH₃COO⁻, (NH₄ ⁺)SO₄ ²⁻, and (NH₄ ⁺)₃PO₄ ³⁻.

The “leaving group” refers to a substituent that is eliminated throughnucleophilic reaction. Examples thereof include halogen, —O—SO₂—CH₃,—O—SO₂—CF₃, —O—SO₂-Ph, and —O—SO₂-Ph-CH₃. The “leaving group” ispreferably halogen.

(In this context, Ph represents a phenyl group.)

Examples of the salt include basic salts or acidic salts.

Examples of the basic salts include: alkali metal salts such as sodiumsalt, potassium salt, and lithium salt; alkaline earth metal salts suchas calcium salt and magnesium salt;

ammonium salt; aliphatic amine salts such as trimethylamine salt,triethylamine salt, dicyclohexylamine salt, ethanolamine salt,diethanolamine salt, triethanolamine salt, procaine salt, megluminesalt, diethanolamine salt, and ethylenediamine salt; aralkylamine saltssuch as N,N-dibenzylethylenediamine and benethamine salt;heterocyclic aromatic amine salts such as pyridine salt, picoline salt,quinoline salt, and isoquinoline salt;quaternary ammonium salts such as tetramethylammonium salt,tetraethylammonium salt, benzyltrimethylammonium salt,benzyltriethylammonium salt, benzyltributylammonium salt,methyltrioctylammonium salt, and tetrabutylammonium salt; and basicamino acid salts such as arginine salt and lysine salt.

Examples of the acidic salts include: inorganic acid salts such ashydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, andperchlorate; organic acid salts such as acetate, propionate, lactate,maleate, fumarate, tartrate, malate, citrate, and ascorbate; sulfonatessuch as methanesulfonate, isethionate, benzenesulfonate, andp-toluenesulfonate; and acidic amino acids such as aspartate andglutamate.

The salt derived from the carboxyl or hydroxyl group is preferably abasic salt, more preferably an alkali metal salt. Particularly preferredexamples of the salt include sodium salt, lithium salt, and potassiumsalt. The most preferred example of the salt includes sodium salt.

The salt derived from the amine site is preferably an acidic salt, morepreferably an inorganic acid salt. Examples of preferable salts includehydrochloride and sulfate.

Hereinafter, the production method of the present invention will bedescribed.

(Step A)

This step is the step of reacting compound (X1) with compound (V1) toobtain a solution containing compound (X2), as shown below in thereaction formula.

In this context, the “solution” means compound (X2) in a dissolved stateand also encompasses compound (X2) in a suspension or slurry form inwhich the compound is dispersed without being completely dissolved. Thisholds true for the description below, and the “solution” according tothe present specification encompasses suspension and slurry forms.

(wherein each symbol is as defined above).

The compound (X1) may be a commercially available reagent or can beobtained by a method known in the art.

When R^(1d) is halogen, nucleophilic substitution reaction may beperformed, if desired in the presence of a base, in a solventsupplemented with an alcohol reagent such as a lower alcohol optionallysubstituted by substituent E, a carbocyclyl lower alkyl alcoholoptionally substituted by substituent E, a heterocyclyl lower alkylalcohol optionally substituted by substituent E, or (R^(1e))₃Si—OH toobtain compound (X1) wherein R^(1d) is lower alkyloxy optionallysubstituted by substituent E, carbocyclyl lower alkyloxy optionallysubstituted by substituent E, heterocyclyl lower alkyloxy optionallysubstituted by substituent E, or —OSi(R^(1e))₃.

Examples of the “lower alkyloxy optionally substituted by substituent E”represented by R^(1d) include methoxy, ethoxy, isopropoxy,trichloromethoxy, and trifluoromethoxy. Methoxy is preferred.

Examples of the “carbocyclyl lower alkyloxy optionally substituted bysubstituent E” represented by R^(1d) include benzyloxy, phenethyloxy,2,4-difluorobenzyloxy, and 4-methoxybenzyloxy. Benzyloxy is preferred.

Examples of the “heterocyclyl lower alkyloxy optionally substituted bysubstituent E” represented by R^(1d) include pyridylmethyloxy.

R^(1d) in preferred embodiments is hydrogen, chloro, bromo, methoxy, orbenzyloxy.

When R^(1d) is —OSi(R^(1e))₃, R^(1e) in preferred embodiments is methyl,ethyl, n-propyl, isopropyl, tert-butyl, or the like.

Examples of the “lower alkyl optionally substituted by substituent E”represented by R^(2d) include methyl, ethyl, n-propyl, isopropyl, andtert-butyl.

Examples of the “carbocyclyl lower alkyl optionally substituted bysubstituent E” represented by R^(2d) include benzyl and 4-methoxybenzyl.

Examples of the “heterocyclyl lower alkyl optionally substituted bysubstituent E” represented by R^(2d) include pyridylmethyl.

R^(2d) in preferred embodiments is methyl, ethyl, n-propyl, isopropyl,tert-butyl, benzyl, 4-methoxybenzyl, or the like.

The reaction solvent used in the nucleophilic substitution reaction forobtaining the compound (X1) is preferably an aprotic solvent. Examplesthereof include acetonitrile, tetrahydrofuran, dioxane, diethyl ether,dichloromethane, chloroform, toluene, xylene, ethyl acetate,N,N-dimethylformamide, N,N-dimethylacetamide, dimethylimidazolidinone,and mixed solvents thereof.

The base can be any base capable of deprotonating the alcohol reagent.Examples thereof include n-butyllithium, tert-butyllithium, sodiumtert-butoxide, potassium-tert-butoxide, sodium tert-pentoxide, sodiummethoxide, sodium ethoxide, sodium hydride, lithium diisopropylamide,and lithium bis(trimethylsilyl)amide.

The amount of the base is approximately 1.0 to 3.0 molar equivalentswith respect to compound (X1) wherein R^(1d) is halogen.

The amount of the alcohol reagent is approximately 0.5 to 1.5 molarequivalents with respect to compound (X1) wherein R^(1d) is halogen.

The reaction temperature is usually 0° C. to reflux temperature,preferably room temperature to 50° C.

The reaction time is usually 10 minutes to 50 hours, preferably 1 to 4hours.

The compound (V1) can be obtained as a commercially available reagent orby a method known in the art.

Examples of the “lower alkyl optionally substituted by substituent E”represented by P^(d) include methyl, ethyl, and trifluoromethyl. P^(d)in preferred embodiments is methyl.

Examples of the “lower alkyloxy optionally substituted by substituent E”represented by R^(3d) include methoxy and ethoxy.

When R^(3d) is —N(R^(3e))₂, examples of the “lower alkyl optionallysubstituted by substituent E” represented by R^(3e) include methyl,ethyl, and trifluoromethyl.

R^(3d) in preferred embodiments is —N(CH₃)₂, —OCH₃, or pyrrolidinyl.

Examples of the solvent of the reaction include acetonitrile,tetrahydrofuran, dioxane, diethyl ether, dichloromethane, chloroform,toluene, xylene, ethyl acetate, N,N-dimethylformamide,N,N-dimethylacetamide, dimethylimidazolidinone, and mixed solventsthereof.

The amount of the compound (V1) used is approximately 1.0 to 3.0 molarequivalents with respect to compound (X1), or the compound (V1) may beused as a solvent.

The reaction temperature is usually 0° C. to reflux temperature,preferably room temperature.

The reaction time is usually 30 minutes to 50 hours, preferably 2 to 8hours.

The compound (X2) may be isolated by a general purification method(extraction, distillation, column chromatography, crystallization, etc.)or can also be used in the next reaction without being isolated.

(Step A′)

Compound (X2) may be obtained through the following reaction:

(wherein R^(5d) is halogen, lower alkyloxy optionally substituted bysubstituent E, or —O—SO₂—R^(5e); and each of the other symbols is asdefined above).

The compound (Z1) may be a commercially available reagent or can beobtained by a method known in the art.

Examples of the “lower alkyl optionally substituted by substituent E”represented by R^(2d) include methyl, ethyl, n-propyl, isopropyl, andtert-butyl.

Examples of the “carbocyclyl lower alkyl optionally substituted bysubstituent E” represented by R^(2d) include benzyl and 4-methoxybenzyl.

Examples of the “heterocyclyl lower alkyl optionally substituted bysubstituent E” represented by R^(2d) include pyridylmethyl.

R^(2d) in preferred embodiments is methyl, ethyl, n-propyl, isopropyl,tert-butyl, benzyl, 4-methoxybenzyl, or the like.

Examples of the “lower alkyloxy optionally substituted by substituent E”represented by R^(3d) include methoxy and ethoxy.

When R^(3d) is —N(R^(3e))₂, examples of the “lower alkyl optionallysubstituted by substituent E” represented by R^(3e) include methyl,ethyl, and trifluoromethyl.

R^(3d) in preferred embodiments is —N(CH₃)₂, —OCH₃, or pyrrolidinyl.

The compound (Z2) may be a commercially available reagent or can beobtained by a method known in the art.

Examples of the “lower alkyloxy optionally substituted by substituent E”represented by R^(1d) include methoxy, ethoxy, isopropoxy,trichloromethoxy, and trifluoromethoxy. Methoxy is preferred.

Examples of the “carbocyclyl lower alkyloxy optionally substituted bysubstituent E” represented by R^(1d) include benzyloxy, phenethyloxy,2,4-trifluorobenzyloxy, and 4-methoxybenzyloxy. Benzyloxy is preferred.

Examples of the “heterocyclyl lower alkyloxy optionally substituted bysubstituent E” represented by R^(1d) include pyridylmethyloxy.

R^(1d) in preferred embodiments is hydrogen, chloro, bromo, methoxy, orbenzyloxy.

Examples of preferred embodiments of R^(5d) include chloro, bromo,methoxy, ethoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, andp-toluenesulfonyloxy.

Examples of the solvent of the reaction include acetonitrile,tetrahydrofuran, dioxane, diethyl ether, dichloromethane, chloroform,toluene, xylene, ethyl acetate, N,N-dimethylformamide,N,N-dimethylacetamide, dimethylimidazolidinone, and mixed solventsthereof.

The amount of the compound (Z2) used is approximately 1.0 to 3.0 molarequivalents with respect to compound (Z1).

The reaction temperature is usually −10° C. to reflux temperature,preferably room temperature.

The reaction time is usually 10 minutes to 10 hours, preferably 1 to 4hours.

Tertiary amine is added, if necessary. Examples of the tertiary amineinclude pyridine, triethylamine, dimethylaminopyridine, andN-methylmorpholine.

The compound (X2) may be isolated by a general purification method(extraction, distillation, column chromatography, crystallization, etc.)or can also be used in the next reaction without being isolated.

(Step B)

This step is the step of reacting compound (X2) with compound (V2), ifdesired in the presence of a base, to obtain a solution containingcompound (X3) or a salt thereof, as shown below in the reaction formula:

(wherein each symbol is as defined above).

Examples of the “lower alkyloxy optionally substituted by substituent E”represented by R^(1d) include methoxy, ethoxy, isopropoxy,trichloromethoxy, and trifluoromethoxy. Methoxy is preferred.

Examples of the “carbocyclyl lower alkyloxy optionally substituted bysubstituent E” represented by R^(1d) include benzyloxy, phenethyloxy,2,4-trifluorobenzyloxy, and 4-methoxybenzyloxy. Benzyloxy is preferred.

Examples of the “heterocyclyl lower alkyloxy optionally substituted bysubstituent E” represented by R^(1d) include pyridylmethyloxy.

R^(1d) in Preferred embodiments is hydrogen, chloro, bromo, methoxy, orbenzyloxy.

Examples of the “lower alkyl optionally substituted by substituent E”represented by R^(2d) include methyl, ethyl, n-propyl, isopropyl, andtert-butyl.

Examples of the “carbocyclyl lower alkyl optionally substituted bysubstituent E” represented by R^(2d) include benzyl and 4-methoxybenzyl.

Examples of the “heterocyclyl lower alkyl optionally substituted bysubstituent E” represented by R^(2d) include pyridylmethyl.

R^(2d) in preferred embodiments is methyl, ethyl, n-propyl, isopropyl,tert-butyl, benzyl, 4-methoxybenzyl, or the like.

Examples of the “lower alkyloxy optionally substituted by substituent E”represented by R^(3d) include methoxy and ethoxy.

Examples of the “lower alkyl optionally substituted by substituent E”represented by R^(3e) include methyl, ethyl, and trifluoromethyl.

R^(3d) in preferred embodiments is —N(CH₃)₂, —OCH₃, or pyrrolidinyl.

The compound (V2) can be obtained as a commercially available reagent orby a method known in the art.

Examples of the “lower alkyl optionally substituted by substituent E”represented by R^(4d) include methyl, ethyl, n-propyl, isopropyl, andtert-butyl.

Examples of the “carbocyclyl lower alkyl optionally substituted bysubstituent E” represented by R^(4d) include benzyl and 4-methoxybenzyl.

Examples of the “heterocyclyl lower alkyl optionally substituted bysubstituent E” represented by R^(4d) include pyridylmethyl.

Examples of preferred embodiments of R^(4d) include methyl, ethyl,n-propyl, isopropyl, tert-butyl, benzyl, and 4-methoxybenzyl.Particularly, methyl or ethyl is preferred.

Examples of preferred embodiments of R^(5d) include chloro, bromo,methoxy, ethoxy, acetoxy, methanesulfonyloxy,trifluoromethanesulfonyloxy, and p-toluenesulfonyloxy. Particularly,chloro, methoxy, or ethoxy is preferred.

Examples of the reaction solvent include acetonitrile, tetrahydrofuran,dioxane, toluene, xylene, ethyl acetate, N,N-dimethylformamide,N,N-dimethylacetamide, dimethylimidazolidinone, N-methylmorpholine,N-methylpyrrolidinone, and mixed solvents thereof.

Examples of the base include n-butyllithium, tert-butyllithium, sodiumtert-butoxide, potassium-tert-butoxide, sodium tert-pentoxide, sodiummethoxide, sodium ethoxide, sodium hydride, lithium diisopropylamide,and lithium bis(trimethylsilyl)amide.

The amount of the base used is approximately 1.0 to 5.0 molarequivalents with respect to compound (X2).

The amount of the compound (V2) used is approximately 1.5 to 5.0 molarequivalents with respect to compound (X2), or the compound (V2) may beused as a solvent.

The reaction temperature is usually −80° C. to reflux temperature,preferably −20° C. to 50° C.

The reaction time is usually 30 minutes to 50 hours, preferably 2 to 12hours.

The compound (X3) may be isolated by a general purification method(extraction, distillation, column chromatography, crystallization, etc.)or can also be used in the next reaction without being isolated.Preferably, the compound (X3) is isolated as crystals free fromimpurities by crystallization.

(Step B′)

This step is the step of reacting compound (X2) with compound (V2) andcompound (V2′), if desired in the presence of a base, to obtain compound(X4′) or a salt thereof as shown below in the reaction formula:

(wherein each symbol is as defined above).

Examples and preferred embodiments of R^(1d), R^(2d), R^(3d), R^(4d),and R^(5d) in the formulae (X2) and (V2) are the same as above.

Examples of the reaction solvent include acetonitrile, tetrahydrofuran,dioxane, toluene, xylene, ethyl acetate, N,N-dimethylformamide,N,N-dimethylacetamide, dimethylimidazolidinone, N-methylmorpholine,N-methylpyrrolidinone, and mixed solvents thereof.

Examples of the base include n-butyllithium, tert-butyllithium, sodiumtert-butoxide, potassium-tert-butoxide, sodium tert-pentoxide, sodiummethoxide, sodium ethoxide, sodium hydride, lithium diisopropylamide,and lithium bis(trimethylsilyl)amide.

The amount of the base used is approximately 1.0 to 5.0 molarequivalents with respect to compound (X2).

The amount of the compound (V2) used is approximately 1.0 to 3.0 molarequivalents with respect to compound (X2), or the compound (V2) may beused as a solvent.

The reaction temperature is usually −80° C. to reflux temperature,preferably −20° C. to 30° C.

The reaction time is usually 10 minutes to 10 hours, preferably 30minutes to 4 hours.

Subsequently, compound (V2′) is added to the reaction solution andreacted therewith.

Examples of the compound (V2′) include ammonium acetate, ammoniumchloride, ammonium bromide, ammonium sulfate, ammonium bisulfate,ammonium formate, ammonium nitrate, ammonium hydroxide, ammoniumphosphate, NH₄ ⁺BF₄ ⁻, NH₄ ⁺PF₆ ⁻, NH₄ ⁺Ph-SO₃ ⁻, NH₄ ⁺CH₃-Ph-SO₃ ⁻, andNH₄ ⁺CH₃—SO₃ ⁻. The compound (V2′) is preferably ammonium acetate,ammonium chloride, ammonium sulfate, ammonium bisulfate, or ammoniumformate. (In this context, Ph represents a phenyl group.)

The amount of the compound (V2′) used is approximately 1.0 to 3.0 molarequivalents with respect to compound (X2).

The reaction temperature is usually 0° C. to reflux temperature,preferably 20° C. to 80° C.

The reaction time is usually 10 minutes to 10 hours, preferably 30minutes to 4 hours.

The compound (X4′) may be isolated by a general purification method(extraction, distillation, column chromatography, crystallization, etc.)or can also be used in the next reaction without being isolated.Preferably, the compound (X4′) is isolated as crystals free fromimpurities by crystallization.

(Step C)

This step is the step of reacting compound (X3) or a salt thereof withcompound (V3) or a salt thereof to obtain compound (X4) or a saltthereof, as shown below in the reaction formula:

(wherein each symbol is as defined above).

Examples and preferred embodiments of R^(1d), R^(2d), and R^(4d) in theformula (X3) are the same as those described above in Step B.

The compound (V3) can be obtained as a commercially available reagent orby a method known in the art.

Examples of the “lower alkyl optionally substituted by substituent E”represented by R^(6d) include HC(═O)—CH₂—, CH(—OH)₂—CH₂—,CH₃O—CH(—OH)—CH₂—, dimethoxyethyl, diethoxyethyl, HO—CH₂—CH(—OH)—CH₂—,

Examples of the “lower alkenyl optionally substituted by substituent E”represented by R^(6d) include CH₂═CH—CH₂—.

Examples of the reaction solvent include acetonitrile, tetrahydrofuran,dioxane, toluene, xylene, ethyl acetate, N,N-dimethylformamide,N,N-dimethylacetamide, dimethylimidazolidinone, N-methylmorpholine,N-methylpyrrolidinone, methanol, ethanol, isopropanol, and mixedsolvents thereof.

The amount of the compound (V3) used is approximately 1.0 to 2.0 molarequivalents with respect to compound (X3).

The reaction temperature is usually 0° C. to reflux temperature,preferably 20° C. to 70° C.

The reaction time is usually 30 minutes to 50 hours, preferably 2 to 12hours.

When R^(6d) in the formed compound (X4) is not an aldehyde group or agroup having an equivalent thereof, such as HC(═O)—CH₂—,CH₃O—CH(—OH)—CH₂—, or CH(—OH)₂—CH₂—, this moiety can be converted toHC(═O)—CH₂—, CH₃O—CH(—OH)—CH₂—, or CH(—OH)₂—CH₂—, which is an aldehydegroup or a group having an equivalent thereof, by deprotection methodsfor protective groups in aldehyde groups described in Protective Groupsin Organic Synthesis, Theodora W Greene (John Wiley & Sons) or a methodknown in the art as described in International Publication No. WO2006/116764 or 2006/088173.

When R^(6d) in compound (X4) is, for example, dimethoxyethyl, thismoiety can be converted to HC(═O)—CH₂— by the addition of an acid to thesolution containing compound (X4). The acid is not particularly limitedand is exemplified by hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, p-toluenesulfonic acid,methanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid,maleic acid, and oxalic acid. The amount of the acid used is 2.0 to 10.0molar equivalents with respect to compound (X4). Acetic acid or formicacid may be used as a solvent and may be used as a mixture with any ofthe acids described above.

The reaction temperature is usually approximately 0° C. to 80° C.,preferably 10° C. to 40° C.

The reaction time is usually 30 minutes to 50 hours, preferably 2 to 12hours.

When the amino group is protected with an amino protective group, acompound with a deprotected amino group can also be obtained bydeprotection methods for protective groups in amino groups described inProtective Groups in Organic Synthesis, Theodora W Greene (John Wiley &Sons) or a method known in the art. The order of deprotection reactionscan be changed appropriately.

When R^(6d) is an amino protective group, the amino protective group incompound (X4) can be subjected to deprotection reaction, followed byreaction with compound (V3′) in the subsequent step, as in Step C′ shownbelow, to obtain the compound (X4) of interest.

The compound (X4) may be isolated by a general purification method(extraction, distillation, column chromatography, crystallization, etc.)or can also be used in the next reaction without being isolated.Preferably, the compound (X4) is isolated as crystals free fromimpurities by crystallization.

(Step C′)

This step is the step of reacting compound (X4′) or a salt thereof withcompound (V3′), if desired in the presence of a base, to obtain compound(X4) or a salt thereof, as shown below in the reaction formula:

(wherein each symbol is as defined above).

Examples and preferred embodiments of R^(1d), R^(2d), R^(4d), and R^(6d)in the formulae (X4′) and (V3′) are the same as those described above inStep B′ and Step C.

Examples of the “leaving group” represented by L^(d) include halogen,—O—SO₂—CH₃, —O—SO₂—CF₃, —O—SO₂-Ph, and —O—SO₂-Ph-CH₃. Halogen ispreferred. (In this context, Ph represents a phenyl group.)

When R^(6d) in the formed compound (X4) does not have an aldehyde groupor an equivalent thereof, such as HC(═O)—CH₂—, CH₃O—CH(—OH)—CH₂—, orCH(—OH)₂—CH₂—, the method of converting this moiety to the aldehydegroup or the equivalent thereof is also the same as above.

Examples of the reaction solvent include acetonitrile, ethyl acetate,N,N-dimethylformamide, N,N-dimethylacetamide, dimethylimidazolidinone,N-methylmorpholine, N-methylpyrrolidinone, and mixed solvents thereof.

Examples of the base include potassium carbonate, cesium carbonate,sodium hydride, n-butyllithium, tert-butyllithium, sodium tert-butoxide,potassium-tert-butoxide, sodium tert-pentoxide, sodium methoxide,triethylamine, 4-dimethylaminopyridine, diisopropylethylamine, and DBU(1,8-diazabicyclo[5.4.0]undec-7-ene).

The amount of the base used is approximately 1.0 to 5.0 molarequivalents with respect to compound (X4′).

The amount of the compound (V3′) used is approximately 1.0 to 4.0 molarequivalents with respect to compound (X4′), or the compound (V3′) may beused as a solvent.

The reaction temperature is usually 0° C. to reflux temperature,preferably 20° C. to 80° C.

The reaction time is usually 30 minutes to 24 hours, preferably 1 to 8hours.

The compound (X4) may be isolated by a general purification method(extraction, distillation, column chromatography, crystallization, etc.)or can also be used in the next reaction without being isolated.Preferably, the compound (X4) is isolated as crystals free fromimpurities by crystallization.

(Step D)

This step is the step of reacting compound (X4) or a salt thereof withcompound (V5) or compound (V5′), if desired in the presence of an acid,to obtain compound (X5) or compound (X5′), or a salt thereof, as shownbelow in the reaction formula:

(wherein R^(1d), R^(2d), and R^(4d) are as defined above; R^(6d) is analdehyde group or an equivalent thereof, such as HC(═O)—CH₂—,CH₃O—CH(—OH)—CH₂—, or CH(—OH)₂—CH₂—; and when R^(6d) is not the aldehydeor the equivalent thereof, the method described above in Step C isperformed).

Examples and preferred embodiments of R^(1d), R^(2d), and R^(4d) in theformulae (X4), (X5), and (X5′) are the same as above.

The compound (V5) and the compound (V5′) are commercially availablereagents.

Examples of the reaction solvent include acetonitrile, tetrahydrofuran,dioxane, toluene, xylene, ethyl acetate, N,N-dimethylformamide,N,N-dimethylacetamide, dimethylimidazolidinone, N-methylmorpholine,N-methylpyrrolidinone, and mixed solvents thereof.

Examples of the acid include acetic acid, trifluoroacetic acid, formicacid, and methane sulfonic acid. The amount of the acid used is 0.5 to3.0 molar equivalents with respect to compound (X4).

The amount of the compound (V5) or the compound (V5′) used isapproximately 1.0 to 2.0 molar equivalents with respect to compound(X4), or the compound (V5) or the compound (V5′) may be used as asolvent.

In this reaction, 1.0 to 5.0 molar equivalents of an alcohol reagent maybe added, if desired, to thereby improve the reaction rate. The alcoholreagent is preferably methanol, ethanol, or isopropanol, particularlypreferably methanol.

The reaction temperature is usually 20° C. to reflux temperature,preferably 60° C. to 80° C.

The reaction time is usually 30 minutes to 24 hours, preferably 1 to 8hours.

The compound (X5) or the compound (X5′) may be isolated by a generalpurification method (extraction, distillation, column chromatography,crystallization, etc.) or can also be used in the next reaction withoutbeing isolated. Preferably, the compound (X5) or the compound poi) isisolated as crystals free from impurities by crystallization.

(Step E)

This step is the step of reacting compound (X5) or compound (X5′), or asalt thereof with compound (V6) or a salt thereof to obtain compound(X6) or compound (X6′), as shown below in the reaction formula:

(wherein R^(1d) and R^(2d) are as defined above; R^(X) is carbocyclyloptionally substituted by substituent E, heterocyclyl optionallysubstituted by substituent E, carbocyclyl lower alkyl optionallysubstituted by substituent E, or heterocyclyl lower alkyl optionallysubstituted by substituent E).

Examples of the “carbocyclyl optionally substituted by substituent E”represented by R^(X) include phenyl, 2,4-difluorophenyl, and cyclohexyl.

Examples of the “heterocyclyl optionally substituted by substituent E”represented by R^(X) include pyridyl, morpholinyl, and isoxazolyl.

Examples of the “carbocyclyl lower alkyl optionally substituted bysubstituent E” represented by R^(X) include benzyl, 4-methoxybenzyl, and2,4-difluorobenzyl.

Examples of the “heterocyclyl lower alkyl optionally substituted bysubstituent E” represented by R^(X) include pyridylmethyl andisoxazolylmethyl.

Preferred examples of substituent E for the “carbocyclyl optionallysubstituted by substituent E”, “heterocyclyl optionally substituted bysubstituent E”, “carbocyclyl lower alkyl optionally substituted bysubstituent E”, and “heterocyclyl lower alkyl optionally substituted bysubstituent E” represented by R^(X) include halogen, cyano, hydroxy,carboxy, formyl, amino, oxo, nitro, lower alkyl, halogeno lower alkyl,lower alkyloxy, halogeno lower alkyloxy, lower alkyloxy lower alkyl,lower alkyloxy lower alkyloxy, lower alkylcarbonyl, loweralkyloxycarbonyl, lower alkyloxycarbonylamino, lower alkylamino, loweralkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, andlower alkylsulfonylamino More preferred examples thereof includehalogen, cyano, hydroxy, carboxy, formyl, amino, lower alkyl, halogenolower alkyl, and lower alkyloxy. Further preferred examples thereofinclude halogen, lower alkyl, and lower alkyloxy. Halogen is mostpreferred.

R^(X) in preferred embodiments is “carbocyclyl lower alkyl optionallysubstituted by substituent E” or “heterocyclyl lower alkyl optionallysubstituted by substituent E”. R^(X) in more preferred embodiments is“carbocyclyl lower alkyl optionally substituted by substituent E”. R^(X)in further preferred embodiments is “carbocyclyl lower alkyl optionallysubstituted by halogen”. R^(X) in the most preferred embodiment is2,4-difluorobenzyl.

When R^(1d) is hydrogen, this moiety can be converted appropriately tohalogen using a halogenating agent such as N-bromosuccinimide,N-chlorosuccinimide, or sulfuryl chloride.

R^(1d) can be selected appropriately according to the reactivity of thereaction substrate. The order of these reactions can be changedappropriately.

When R^(2d) is hydrogen, compound (X6) or compound (X6′) can be inducedthrough general dehydration-condensation reaction (e.g., a method usinga condensation agent, an acid chloride formation method, or an acidanhydride formation method) of the carboxyl group and compound (V6). Forexample, amide compound (X6) or compound (X6′) can be obtained throughreaction at 0° C. to 60° C., preferably 10° C. to 40° C., for 1 hour to48 hours, preferably 1 hour to 24 hours, in the presence of adehydration-condensation agent such as dicyclohexylcarbodiimide,carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole,4-(4, 6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate, or WSC.

When R^(2d) is not hydrogen, this moiety is converted to a carboxylgroup through general deprotection reaction of the carboxyl protectivegroup. Compound (X6) or compound (X6′) can be induced through the samedehydration-condensation reaction as above of the formed carboxyl groupand compound (V6). The carboxyl protective group is exemplified bycarboxyl protective groups described in, for example, Protective Groupsin Organic Synthesis, Theodora W Greene (John Wiley & Sons). Preferredexamples thereof include methyl, ethyl, tert-butyl, methoxymethyl,allyl, benzyl, and p-methoxybenzyl groups.

When R^(2d) is “lower alkyl optionally substituted by substituent E”,compound (X6) or compound (X6′) can also be induced through aminolysisreaction using compound (V6).

The compound (X6) or the compound (X6′) may be isolated by a generalpurification method (extraction, distillation, column chromatography,crystallization, etc.) or can also be used in the next reaction withoutbeing isolated. Preferably, the compound (X6) or the compound (X6′) isisolated as crystals free from impurities by crystallization.

Compound X6 or compound X6′ may also be obtained by the following StepE′ and Step D′:

(wherein R^(1d), R^(2d), R^(4d), R^(6d), and R^(X) are as defined above;R^(6d) is an aldehyde group or an equivalent thereof such asHC(═O)—CH₂—, CH₃O—CH(—OH)—CH₂—, or CH(—OH)₂—CH₂—; and when R^(6d) is notthe aldehyde or the equivalent thereof, the method described above inStep C is performed).(Step E′)

This step is the step of reacting compound (X5) or compound (X4), or asalt thereof with compound (V6) or a salt thereof to obtain compound(X4″).

Examples and preferred embodiments of R^(1d), R^(2d), R^(4d), and R^(X)are the same as above.

When R^(2d) is hydrogen, compound (X4″) can be induced through generaldehydration-condensation reaction (e.g., a method using a condensationagent, an acid chloride formation method, or an acid anhydride formationmethod) of the carboxyl group and compound (V6). For example, amidecompound (X6) can be obtained through reaction at 0° C. to 60° C.,preferably 10° C. to 40° C., for 1 hour to 48 hours, preferably 1 hourto 24 hours, in the presence of a dehydration-condensation agent such asdicyclohexylcarbodiimide, carbonyldiimidazole,dicyclohexylcarbodiimide-N-hydroxybenzotriazole,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate, or WSC.

When R^(2d) is not hydrogen, this moiety is converted to a carboxylgroup through general deprotection reaction of the carboxyl protectivegroup. Compound (X4″) can be induced through the samedehydration-condensation reaction as above of the formed carboxyl groupand compound (V6). The carboxyl protective group is exemplified bycarboxyl protective groups described in, for example, Protective Groupsin Organic Synthesis, Theodora W Greene (John Wiley & Sons). Preferredexamples thereof include methyl, ethyl, tert-butyl, methoxymethyl,allyl, benzyl, and p-methoxybenzyl groups. A methyl group isparticularly preferred.

When R^(2d) is “lower alkyl optionally substituted by substituent E”,compound (X4″) can also be induced through aminolysis reaction ofcompound (V6).

(Step D′)

This step is the step of reacting the compound (X4′) obtained in Step E′with compound (V5) or compound (V5′), if desired in the presence of anacid, to obtain compound (X6) or compound (X6′), or a salt thereof.

(Step F)

This step is the step of obtaining compound (Y1) or compound (Y2), or asalt thereof from compound (X6) or compound (X6′), as shown below in thereaction formula:

(wherein each symbol is as defined above).

Examples and preferred embodiments of R^(X) are as defined above.

When R^(1d) is lower alkyloxy optionally substituted by substituent E,carbocyclyl lower alkyloxy optionally substituted by substituent E,heterocyclyl lower alkyloxy optionally substituted by substituent E, or—OSi(R^(1e))₃, this moiety can be converted to a hydroxy group throughhydroxy deprotection reaction known in the art described in, forexample, Protective Groups in Organic Synthesis, Theodora W Greene (JohnWiley & Sons).

Specifically, when R^(1d) is methyloxy, this moiety can be converted toa hydroxy group using a reagent such as (CH₃)₃—Si—I, BBr₃, or BF₃.Et₂O.When R^(1d) is benzyloxy, this moiety can be converted to a hydroxygroup using Pd—C/H₂ gas, a Raney-Ni reagent, or the like. When R^(1d) is—OSi(CH₃)₃, this moiety can be converted to a hydroxy group using atetramethylammonium fluoride reagent.

When R^(1d) is halogen, this moiety can be converted to a hydroxy groupby reaction with potassium trimethylsilanolate or lithiumtrimethylsilanolate and the subsequent addition of an aqueous solutionof an inorganic acid. Examples of other conditions for the conversionreaction of halogen to a hydroxy group also include use of sodiumhydride/water (Bioorganic Medicinal Chemistry Letters, 17, 1713, 2007),potassium hydroxide/tris(dibenzylideneacetone)dipalladium(Pd₂dba₃)/di-tert-butylarylphosphine (Journal of the American ChemicalSociety, 128, 10694, 2006), potassium phosphate hydrate(K₃PO₄.H₂O)/tris(dibenzylideneacetone)dipalladium(Pd₂dba₃)/tri-tert-butylphosphine (Tetrahedron Letters, 48, 473, 2007).As described above, the halogen represented by R^(1d) in the startingmaterial may be derivatized directly. Thus, this approach requires asmaller number of reaction steps and may construct a more advantageousindustrial production method, compared with the method involving alcoholprotection and/or deprotection reactions.

When R^(1d) is hydrogen, this R^(1d) may be converted to halogen throughreaction with a halogenating agent such as N-bromosuccinimide,N-chlorosuccinimide, or sulfuryl chloride, followed by reaction withpotassium trimethylsilanolate or lithium trimethylsilanolate and thesubsequent addition of an aqueous solution of an inorganic acid in thesame way as above to induce a hydroxy group. Accordingly, R^(1d) can beselected appropriately from among these substituents according to thereactivity of the reaction substrate.

In the step, the order of these reactions can be changed appropriately.

The compound (Y1) or the compound (Y2) can be isolated by a generalpurification method (extraction, distillation, column chromatography,crystallization, etc.).

The compound (Y1) or the compound (Y2) can be converted to a salt by thedesired method. The salt is preferably a basic salt, more preferably analkali metal salt such as sodium salt, potassium salt, or lithium. Themost preferred example thereof includes sodium salt.

The salt of compound (Y1) or compound (Y2) can be deposited bydissolving the compound (Y1) or the compound (Y2) in an organic solventor a mixed solution of an organic solvent and water and adding anaqueous alkali solution or an organic base to the solution, followed bystirring. This dissolution is performed by heating, if necessary. Also,the salt deposition is performed by cooling, if necessary.

For example, ethanol, methanol, isopropyl alcohol, acetone,acetonitrile, tetrahydrofuran, or dichloromethane may be used as theorganic solvent.

In the present invention, preferably, the steps described above can becombined arbitrarily to obtain compound (Y1) or compound (Y2), or a saltthereof. Also, one or two or more chemical reactions well known by thoseskilled in the art may be combined appropriately before and/or aftereach step.

Hereinafter, the present invention will be described more specificallywith reference to Examples and Test Examples of the present invention.However, the present invention is not limited to them. Each symbol usedin Examples is as follows:

Me: Methyl

Et: Ethyl

Bn: Benzyl

Ph: Phenyl

DMI: Dimethylimidazolidinone

THF: Tetrahydrofuran

WSC: N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide

HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

DBU: 1,8-diazabicyclo[5.4.0]-7-undecene

DMF: N,N-dimethylformamide

HOBt: 1-hydroxybenzotriazole

NBS: N-bromosuccinimide

Example 1

Step 1

A THF (3 ml) solution of benzyl alcohol (1.00 g, 9.25 mmol) was added toa THF (4 ml) suspension of sodium tert-pentoxide (2.55 g, 23.2 mmol) atroom temperature in a nitrogen atmosphere, and the mixture was stirredat 40° C. for 2 hours. This reaction solution was cooled in an ice bath,and a THF (3 ml) solution of compound 1A (1.53 g, 10.2 mmol) was addeddropwise thereto at 0-10° C. The reaction solution was stirred at roomtemperature for 2 hours, and 2 N hydrochloric acid (15 ml) was thenadded thereto, followed by extraction two times with ethyl acetate. Thecombined extracts were washed with water, a saturated aqueous solutionof sodium bicarbonate, water, and saturated saline in this order andthen dried over anhydrous sodium sulfate. The solvent was distilled off,and the obtained oil was purified by silica gel column chromatography(n-hexane-ethyl acetate: 4:1, v/v) to obtain 1.89 g (yield: 92%) ofcompound 1B as an oil.

¹H-NMR (CDCl₃) δ: 3.56 (2H, s), 3.71 (3H, s), 4.14 (2H, s), 4.59 (2H,s), 7.27-7.42 (5H, m).

Step 2

Compound 1B (1.80 g, 8.1 mmol) was dissolved in 1,4-dioxane (18 mL). Tothe solution, N,N-dimethylformamide dimethyl acetal (1.45 g, 12.2 mmol)was added, and the mixture was stirred at room temperature for 6 hours.The reaction solution was concentrated under reduced pressure. Then, theresidue was purified by silica gel column chromatography (n-hexane-ethylacetate: 1:4, v/v) to obtain 1.77 g (yield: 79%) of compound 1C as anoil.

¹H-NMR (CDCl₃) δ: 2.90 (3H, br), 3.25 (3H, br), 3.69 (3H, s), 4.45 (2H,s), 4.59 (2H, s), 7.24-7.40 (5H, m), 7.73 (s, 1H).

Step 3

Sodium tert-butoxide (2.55 g, 23.2 mmol), dimethyl oxalate (639 mg, 5.41mmol), and DMI (3 ml) were added to a three-neck flask in a nitrogenatmosphere, and a DMI (2 ml) solution of compound 1C (0.50 g, 1.80 mmol)was added dropwise thereto at 25-30° C. After stirring at roomtemperature for 7 hours, 2 N hydrochloric acid (10 ml) was addedthereto, and the mixture was stirred at room temperature for 15 hours.After extraction two times with ethyl acetate, the combined extractswere washed with water, a saturated aqueous solution of sodiumbicarbonate, water, and saturated saline in this order and then driedover anhydrous sodium sulfate. The solvent was distilled off, and theobtained residue was purified by silica gel column chromatography(n-hexane-ethyl acetate: 2:1→1:1, v/v) to obtain 488 mg (yield: 85%) ofcompound 1D as white crystals.

¹H-NMR (CDCl₃) δ: 3.89 (3H, s), 3.93 (3H, s), 5.34 (2H, s), 7.32-7.40(3H, m), 7.45-7.49 (2H, m), 8.50 (1H, s).

Example 2

Step 1

A DMI (3 ml) solution of benzyl alcohol (0.66 g, 6.1 mmol) was added toa DMI (4 ml) suspension of sodium tert-pentoxide (1.67 g, 15.2 mmol) atroom temperature in a nitrogen atmosphere, and the mixture was stirredat 40° C. for 2 hours. This reaction solution was cooled in an ice bath,and a DMI (3 ml) solution of compound 2A (1.10 g, 6.68 mmol) was addeddropwise thereto at 0-10° C. The reaction solution was stirred at 0-5°C. for 2 hours and at room temperature for 3 hours, and 2 N hydrochloricacid (15 ml) was then added thereto, followed by extraction two timeswith ethyl acetate. The combined extracts were washed with water, asaturated aqueous solution of sodium bicarbonate, water, and saturatedsaline in this order and then dried over anhydrous sodium sulfate. Thesolvent was distilled off, and the obtained oil was purified by silicagel column chromatography (n-hexane-ethyl acetate: 4:1, v/v) to obtain1.29 g (yield: 90%) of compound 2B as an oil.

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.2 Hz), 3.54 (2H, s), 4.14 (2H, s),4.17 (2H, q, J=7.2 Hz), 4.59 (2H, s), 7.28-7.40 (5H, m).

Step 2

Compound 2B (9.73 g, 41.2 mmol) was dissolved in toluene (45 mL). To thesolution, N,N-dimethylformamide dimethyl acetal (7.36 g, 61.8 mmol) wasadded, and the mixture was stirred at room temperature for 5 hours.Water was added to the reaction solution, followed by extraction twotimes with ethyl acetate. The combined extracts were washed with waterand saturated saline in this order and then dried over anhydrousmagnesium sulfate. The solvent was distilled off, and the obtained oilwas purified by silica gel column chromatography (n-hexane-ethylacetate: 1:1→3:7, v/v) to obtain 7.90 g (yield: 66%) of compound 2C asan oil.

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.2 Hz), 2.95 (3H, br), 3.22 (3H, br),4.15 (2H, q, J=7.2 Hz), 4.45 (2H, s), 4.59 (2H, s), 7.22-7.40 (5H, m),7.73 (1H, s).

Step 3

Sodium tert-butoxide (495 mg, 5.15 mmol) and DMI (2 ml) were added to athree-neck flask in a nitrogen atmosphere, and a DMI (3 ml) solution ofdimethyl oxalate (608 mg, 5.15 mmol) and compound 2C (0.50 g, 1.72 mmol)was added dropwise thereto at 25-30° C. After stirring at roomtemperature for 4 hours, 2 N hydrochloric acid (10 ml) was added, andthe mixture was stirred at room temperature for 15 hours. Afterextraction two times with toluene, the combined extracts were washedwith water, a saturated aqueous solution of sodium bicarbonate, water,and saturated saline in this order and then dried over anhydrous sodiumsulfate. The solvent was distilled off, and the obtained residue waspurified by silica gel column chromatography (n-hexane-ethyl acetate:2:1, v/v) to obtain 420 mg (yield: 74%) of compound 2D as whitecrystals.

¹H-NMR (CDCl₃) δ: 1.39 (3H, t, J=7.2 Hz), 3.88 (3H, s), 4.39 (2H, q,J=7.2 Hz), 5.34 (2H, s), 7.30-7.41 (3H, m), 7.45-7.50 (2H, m), 8.48 (1H,s).

Example 3

Step 1

N,N-dimethylformamide dimethyl acetal (4.9 ml, 36.5 mmol) was addeddropwise to compound 3A (5.0 g, 30.4 mmol) under cooling at 0° C. Afterstirring at 0° C. for 1 hour, 100 ml of ethyl acetate was added to thereaction solution, and the organic layer was washed with a 0.5 N aqueoushydrochloric acid solution (50 ml). The aqueous layer was separated,followed by extraction with ethyl acetate (50 ml). The organic layerswere combined, washed with a saturated aqueous solution of sodiumbicarbonate and saturated saline in this order, and then dried overanhydrous sodium sulfate. The solvent was distilled off, and theobtained residue was purified by silica gel column chromatography(n-hexane-ethyl acetate: 1:1 (v/v)→ethyl acetate) to obtain 4.49 g(yield: 67%) of compound 3B as an oil.

¹H-NMR (CDCl₃)δ: 1.32 (3H, t, J=7.1 Hz), 2.90 (3H, br s), 3.29 (3H, brs), 4.23 (2H, q, J=7.1 Hz), 4.54 (2H, s), 7.81 (1H, s).

Step 2

Lithium hexamethyldisilazide (1.0 M solution in toluene, 49 ml, 49.0mmol) was diluted with tetrahydrofuran (44 ml). A tetrahydrofuran (10ml) solution of compound 3B (4.49 g, 20.4 mmol) was added dropwisethereto under cooling at −78° C., and a tetrahydrofuran (10 ml) solutionof ethyl oxalyl chloride (3.35 g, 24.5 mmol) was then added dropwise tothe mixture. The mixture was stirred at −78° C. for 2 hours and thenheated to 0° C. 2 N hydrochloric acid was added to the reactionsolution, and the mixture was stirred for 20 minutes, followed byextraction with ethyl acetate (200 ml×2). The organic layer was washedwith a saturated aqueous solution of sodium bicarbonate and saturatedsaline and then dried over anhydrous sodium sulfate. The solvent wasdistilled off, and the obtained residue was purified by silica gelcolumn chromatography (n-hexane-ethyl acetate: 7:3→5:5→0:10 (v/v)) toobtain 1.77 g (yield: 31%) of compound 3C as a white solid.

¹H-NMR (CDCl₃)δ: 1.36-1.46 (6H, m), 4.35-4.52 (8H, m), 8.53 (1H, s).

Step 3

Aminoacetaldehyde dimethyl acetal (0.13 ml, 1.20 mmol) was added to anethanol (6 ml) solution of compound 3C (300 mg, 1.09 mmol) at 0° C., andthe mixture was stirred at 0° C. for 1.5 hours, then at room temperaturefor 18 hours, and at 60° C. for 4 hours. The solvent in the reactionsolution was distilled off under reduced pressure, and the obtainedresidue was then purified by silica gel column chromatography(n-hexane-ethyl acetate: 5:5→0:10 (v/v)) to obtain 252 mg (yield: 64%)of compound 3D as an oil.

¹H-NMR (CDCl₃)δ: 1.36-1.47 (6H, m), 3.42 (6H, s), 3.90 (2H, d, J=5.2Hz), 4.37 (3H, q, J=7.2 Hz), 4.50 (2H, q, J=7.2 Hz), 8.16 (1H, s).

Step 4

62% H₂SO₄ (892 mg, 5.64 mmol) was added to a formic acid (10 ml)solution of compound 3D (1.02 g, 2.82 mmol), and the mixture was stirredat room temperature for 16 hours. The formic acid was distilled offunder reduced pressure. To the residue, methylene chloride was added,and the mixture was pH-adjusted to 6.6 by the addition of a saturatedaqueous solution of sodium bicarbonate. The methylene chloride layer wasseparated, while the aqueous layer was subjected to extraction withmethylene chloride. The methylene chloride layers were combined anddried over anhydrous sodium sulfate. The solvent was distilled off toobtain 531.8 mg of compound 3E as a yellow oil.

1H-NMR (CDCl3) δ: 1.28-1.49 (6H, m), 4.27-4.56 (4H, m), 4.84 (2H, s),8.10 (1H, s), 9.72 (1H, s).

Step 5

Methanol (0.20 ml, 5.0 mmol), (R)-3-amino-butan-1-ol (179 mg, 2.0 mmol),and acetic acid (0.096 ml, 1.70 mmol) were added to a toluene (5 ml)solution of compound 3E (531 mg, 1.68 mmol), and the mixture was heatedto reflux for 4 hours. The reaction solution was cooled to roomtemperature, then diluted with chloroform, and then washed with asaturated aqueous solution of sodium bicarbonate. The aqueous layer wassubjected to extraction with chloroform. The chloroform layers werecombined, washed with saturated saline, and then dried over anhydroussodium sulfate. The solvent was distilled off, and the obtained residuewas purified by silica gel column chromatography (chloroform-methanol:100:0→90:10) to obtain 309.4 mg of compound 3F as a brown oil.

1H-NMR (CDCl3) δ: 1.40 (3H, t, J=7.1 Hz), 1.40 (3H, d, J=7.1 Hz),1.55-1.61 (1H, m), 2.19-2.27 (1H, m), 4.00 (1H, d, J=1.5 Hz), 4.03 (1H,d, J=2.5 Hz), 4.10 (1H, dd, J=13.2, 6.3 Hz), 4.26 (1H, dd, J=13.2, 3.8Hz), 4.38 (2H, q, J=7.1 Hz), 5.00-5.05 (1H, m), 5.31 (1H, dd, J=6.4, 3.9Hz), 8.10 (1H, s).

Step 6

Potassium trimethylsilanolate (333 mg, 2.34 mmol) was added to a1,2-dimethoxyethane (2 ml) solution of compound 3F (159 mg, 0.47 mmol),and the mixture was stirred at room temperature for 7 hours. 1 Nhydrochloric acid and saturated saline were added to the reactionsolution, followed by extraction with chloroform. The chloroform layerswere combined and dried over anhydrous sodium sulfate. The solvent wasdistilled off to obtain 34.4 mg (yield: 25%) of compound 3G as an orangepowder.

1H-NMR (CDCl3) δ: 1.46 (3H, d, J=3.5 Hz), 1.58-1.65 (1H, m), 2.26-2.30(1H, m), 4.06-4.10 (2H, m), 4.31 (1H, dd, J=13.8, 5.6 Hz), 4.48 (1H, dd,J=13.6, 3.9 Hz), 5.03 (1H, t, J=6.4 Hz), 5.36 (1H, dd, J=5.5, 4.0 Hz),8.44 (1H, s), 12.80 (1H, s), 14.90 (1H, s).

Step 7

Compound 3G (16 mg, 0.054 mmol) and 2,4-difluorobenzylamine (17 mg, 0.12mmol) were dissolved in N,N-dimethylformamide (1 ml). To the solution,N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (HATU) (53 mg, 0.14 mmol) and N-methylmorpholine(0.031 ml, 0.28 mmol) were added, and the mixture was stirred at roomtemperature for 16 hours. 2,4-difluorobenzylamine (17 mg, 0.12 mmol),HATU (64 mg, 0.17 mmol), and N-methylmorpholine (0.037 ml, 0.34 mmol)were further added thereto, and the mixture was stirred at roomtemperature for additional 16 hours. 0.5 N hydrochloric acid was addedto the reaction solution, followed by extraction with ethyl acetate. Theethyl acetate layers were combined, washed with 0.5 N hydrochloric acidand then with saturated saline, and then dried over anhydrous sodiumsulfate. The solvent was distilled off, and the obtained residue waspurified by preparative high-performance liquid chromatography to obtain12.5 mg (yield: 55%) of compound 3H as an orange solid.

1H-NMR (DMSO-d6) δ: 1.36 (3H, d, J=6.9 Hz), 1.55-1.60 (1H, m), 2.01-2.05(1H, m), 3.92-3.94 (1H, m), 4.04 (1H, t, J=12.6 Hz), 4.38-4.41 (1H, m),4.57-4.60 (1H, m), 4.81-4.83 (1H, m), 5.46-5.49 (1H, m), 7.08-7.11 (1H,m), 7.25-7.30 (1H, m), 7.41 (1H, dd, J=15.3, 8.7 Hz), 8.53 (1H, s),10.38 (1H, s), 12.53 (1H, s).

Example 4

Step 1

N,N-dimethylformamide dimethyl acetal (12.2 ml, 92.2 mmol) was addeddropwise to compound 4A (10.0 g, 76.8 mmol) under cooling at 0° C. Afterstirring at 0° C. for 1.5 hours and then at room temperature for 2.5hours, 100 ml of ethyl acetate was added to the reaction solution, andthe solvent was distilled off. The obtained residue was purified bysilica gel column chromatography (n-hexane-ethyl acetate: 5:5→0:10(v/v)) to obtain 12.45 g (yield: 88%) of compound 4B as an oil.

¹H-NMR (CDCl₃)δ: 1.32 (3H, t, J=7.1 Hz), 2.33 (3H, s), 3.04 (6H, br s),4.23 (2H, q, J=7.2 Hz), 7.68 (1H, s).

Step 2

Lithium hexamethyldisilazide (1.0 M solution in toluene, 24 ml, 24.0mmol) was diluted with tetrahydrofuran (20 ml). A tetrahydrofuran (5 ml)solution of compound 4B (1.85 g, 10.0 mmol) was added dropwise theretounder cooling at −78° C., and a tetrahydrofuran (5 ml) solution of ethyloxalyl chloride (1.34 ml, 12.0 mmol) was then added dropwise thereto.After stirring at −78° C. for 2 hours, 2 N hydrochloric acid was addedto the reaction solution, and the mixture was stirred at roomtemperature for 20 minutes. After extraction with ethyl acetate, theorganic layer was washed with a saturated aqueous solution of sodiumbicarbonate and saturated saline in this order and then dried overanhydrous sodium sulfate. The solvent was distilled off, and theobtained residue was purified by silica gel column chromatography(n-hexane-ethyl acetate: 75:25→455:5 (v/v)) to obtain 1.03 g (yield:43%) of compound 4C as a brown oil.

¹H-NMR (CDCl₃)δ: 1.38 (3H, t, J=7.1 Hz), 1.42 (3H, t, J=7.4 Hz),4.33-4.47 (4H, m), 7.19 (1H, s), 8.54 (1H, s).

Step 3

Aminoacetaldehyde dimethyl acetal (0.34 ml, 3.11 mmol) was added to anethanol (6.8 ml) solution of compound 4C (680 mg, 2.83 mmol) at 0° C.,and the mixture was left standing at room temperature for 16 hours. Thesolvent in the reaction solution was distilled off under reducedpressure, and the obtained residue was then purified by silica gelcolumn chromatography (n-hexane-ethyl acetate: 90:10 (v/v)) to obtain875 mg (yield: 94%) of compound 4D as an oil.

¹H-NMR (CDCl₃)δ: 1.38 (3H, t, J=7.1 Hz), 1.39 (3H, t, J=7.1 Hz), 3.40(6H, s), 4.33 (2H, d, J=4.7 Hz), 4.37 (4H, q, J=7.1 Hz), 4.49 (1H, t,J=4.7 Hz), 7.06 (1H, s), 8.17 (1H, s).

Step 4

N-bromosuccinimide (1.46 g, 8.18 mmol) was added to aN,N-dimethylformamide (10 ml) solution of compound 4D (2.68 g, 8.18mmol), and the mixture was stirred at room temperature for 48 hours. Asaturated aqueous solution of sodium bicarbonate was added to thereaction solution, followed by extraction with ethyl acetate. Theorganic layer was washed with water and saturated saline in this orderand then dried over anhydrous sodium sulfate. The solvent was distilledoff, and the obtained residue was then purified by silica gel columnchromatography (n-hexane-ethyl acetate: 90:10 (v/v)) to obtain 2.83 g(yield: 85%) of compound 4E as an oil.

1H-NMR (CDCl3) δ: 1.41 (3H, t, J=7.1 Hz), 1.48 (3H, t, J=7.1 Hz), 3.42(6H, s), 3.90 (2H, d, J=5.0 Hz), 4.39 (2H, q, J=7.1 Hz), 4.53 (3H, q,J=14.3 Hz), 4.54 (3H, s), 4.57 (3H, t, J=5.4 Hz), 8.19 (1H, s).

Step 5

62% H₂SO₄ (1.74 g, 10.98 mmol) was added to a formic acid (15 ml)solution of compound 4E (2.23 g, 5.49 mmol), and the mixture was stirredat room temperature for 8 hours. A 0.5 N aqueous sodium hydroxidesolution (120 ml) was added thereto, followed by extraction withmethylene chloride. The methylene chloride layers were combined, washedwith saturated saline, and then dried over anhydrous sodium sulfate. Thesolvent was distilled off to obtain 1.31 g of compound 4F as a whitepowder.

1H-NMR (CDCl3) δ: 1.31-1.46 (6H, m), 4.33-4.48 (4H, m), 4.82 (2H, s),8.11 (1H, s), 9.71 (1H, s).

Step 6

Methanol (0.44 ml, 10.9 mmol), (R)-3-amino-butan-1-ol (389 mg, 4.36mmol), and acetic acid (0.21 ml, 3.64 mmol) were added to a toluene (13ml) solution of compound 4F (1.31 g, 3.64 mmol), and the mixture washeated to reflux for 3 hours. The reaction solution was cooled to roomtemperature, then diluted with chloroform, and then washed with asaturated aqueous solution of sodium bicarbonate. The aqueous layer wassubjected to extraction with chloroform. The chloroform layers werecombined, washed with saturated saline, and then dried over anhydroussodium sulfate. The solvent was distilled off, and the obtained residuewas purified by silica gel column chromatography (chloroform-methanol:100:0→90:10) to obtain 1.58 g of compound 4G as an oil.

1H-NMR (CDCl3) δ: 1.40 (3H, d, J=5.7 Hz), 1.56-1.60 (1H, m), 2.19-2.24(1H, m), 3.99 (1H, d, J=2.0 Hz), 4.02 (1H, d, J=2.4 Hz), 4.11 (1H, dd,J=13.3, 6.7 Hz), 4.28 (1H, dd, J=13.3, 3.9 Hz), 4.36 (3H, q, J=7.1 Hz),4.49-4.56 (1H, m), 4.98-5.03 (1H, m), 5.34 (1H, dd, J=6.6, 3.8 Hz), 8.07(1H, s).

Step 7

Potassium trimethylsilanolate (249 mg, 1.95 mmol) was added to a1,2-dimethoxyethane (3 ml) solution of compound 4G (300 mg, 0.78 mmol),and the mixture was stirred at room temperature for 1 hour. Potassiumtrimethylsilanolate (249 mg, 1.95 mmol) was further added thereto, andthe mixture was stirred at 60° C. for additional 1 hour. 1 Nhydrochloric acid and saturated saline were added to the reactionsolution, followed by extraction with chloroform. The chloroform layerswere combined and dried over anhydrous sodium sulfate. The solvent wasdistilled off to obtain 100.3 mg (yield: 43%) of compound 3G as a yellowpowder.

1H-NMR (CDCl3) δ: 1.46 (3H, d, J=3.5 Hz), 1.58-1.65 (1H, m), 2.26-2.30(1H, m), 4.06-4.10 (2H, m), 4.31 (1H, dd, J=13.8, 5.6 Hz), 4.48 (1H, dd,J=13.6, 3.9 Hz), 5.03 (1H, t, J=6.4 Hz), 5.36 (1H, dd, J=5.5, 4.0 Hz),8.44 (1H, s), 12.80 (1H, s), 14.90 (1H, s).

Example 5

Step 1

Compound 5A (598 mg, 4.09 mmol) and N,N-dimethylformamide dimethylacetal (488 mg, 4.09 mmol) were dissolved in toluene (1 ml), and thesolution was stirred at room temperature for 11 hours. The solvent inthe reaction solution was distilled off under reduced pressure, and theobtained residue (containing compound 5B) was used in Step 2 withoutbeing purified.

Step 2

Sodium tert-butoxide (400 mg, 4.16 mmol) was suspended indimethylimidazolidinone (5 ml). To this suspension, adimethylimidazolidinone (5 ml) solution of the crude product obtained inStep 1 was added. Then, a THF (10 ml) solution of dimethyl oxalate (983mg, 8.32 mmol) was added dropwise thereto, and the mixture was stirredat room temperature for 45 minutes. The reaction solution was added to 2N hydrochloric acid-methanol (20 ml), and the mixture was stirred at 0°C. for 20 minutes. Water was added thereto, followed by extraction withethyl acetate. The organic layer was washed with water, a saturatedaqueous solution of sodium bicarbonate, and saturated saline in thisorder and dried over anhydrous sodium sulfate. The solvent was distilledoff, and the obtained residue was then purified by silica gel columnchromatography to obtain 222 mg (yield based on compound 5A: 22%) ofcompound 5C.

¹H-NMR (CDCl₃)δ: 3.91 (3H, s), 3.97 (3H, s), 4.05 (3H, s), 8.50 (1H, s).

Example 6

Step 1

Lithium hexamethyldisilazide (1.0 M solution in toluene, 12 ml, 12.0mmol) was diluted with tetrahydrofuran (11 ml). A tetrahydrofuran (2 ml)solution of compound 6A (1.46 g, 5.0 mmol) was added dropwise theretounder cooling at −78° C., and a tetrahydrofuran (2 ml) solution of ethyloxalyl chloride (0.67 ml, 6.0 mmol) was then added dropwise thereto.After stirring at −78° C. for 2 hours, ammonium acetate (500 mg) andacetic acid (10 ml) were added to the reaction solution, and the mixturewas stirred at 65° C. for 1.5 hours. Water was added to the reactionsolution, followed by extraction with ethyl acetate. The organic layerwas washed with water and a saturated aqueous solution of sodiumbicarbonate in this order and then dried over anhydrous sodium sulfate.The solvent was distilled off, and the obtained residue was purified bysilica gel column chromatography (n-hexane-ethyl acetate: 55:45→45:55(v/v)) to obtain 505.1 mg of compound 6B as a yellow solid. This solidwas washed with isopropyl ether-hexane (1:2) and dried under reducedpressure to obtain 416.8 mg (yield: 24%) of compound 6B as yellowcrystals.

¹H-NMR (CDCl₃)δ: 1.35 (3H, t, J=7.1 Hz), 1.46 (3H, t, J=7.1 Hz), 4.40(2H, q, J=7.2 Hz), 4.50 (2H, q, J=7.1 Hz), 5.20 (2H, s), 7.33-7.41 (3H,m), 7.49-7.52 (2H, m), 8.76 (1H, s), 11.61 (1H, br s).

Step 2

Cesium carbonate (73.3 mg, 0.23 mmol) and bromoacetaldehyde dimethylacetal (38.0 mg, 0.23 mmol) were added to a N,N-dimethylformamide (1 ml)solution of compound 6B (51.8 mg, 0.15 mmol), and the mixture wasstirred overnight at room temperature. Cesium carbonate (73.3 mg, 0.23mmol) and bromoacetaldehyde dimethyl acetal (38.0 mg, 0.23 mmol) werefurther added thereto, and the mixture was stirred at 100° C. foradditional 20 minutes. Water was added to the reaction solution,followed by extraction with ethyl acetate. The organic layer was washedwith water and saturated saline in this order and then dried overanhydrous sodium sulfate. The solvent was distilled off, and theobtained residue was purified by silica gel column chromatography(n-hexane-ethyl acetate: 50:50→30:70 (v/v)) to obtain 35.3 mg (yield:54%) of compound 6C as a colorless oil.

¹H-NMR (CDCl₃)δ: 1.26 (3H, t, J=7.1 Hz), 1.40 (3H, t, J=7.1 Hz), 3.39(6H, s), 3.91 (2H, d, J=5.0 Hz), 4.29 (2H, q, J=7.1 Hz), 4.40 (2H, q,J=7.2 Hz), 4.50 (1H, t, J=5.0 Hz), 5.30 (2H, s), 7.31-7.37 (3H, m),7.43-7.46 (2H, m), 8.12 (1H, s).

Example 7

Step 1

Compound 6A (291 mg, 1.0 mmol) and dimethyl oxalate (354 mg, 3.0 mmol)were dissolved in dimethylimidazolidinone (1.4 ml). To this solution,sodium methoxide (28% solution in methanol, 0.30 ml, 1.5 mmol) wasadded, and the mixture was stirred at room temperature for 2 hours.1,3-dioxolan-2-yl-methylamine (154 mg, 1.5 mmol) and acetic acid (0.29ml, 5.0 mmol) were added thereto, and the mixture was stirred at roomtemperature for 38 hours. A saturated aqueous solution of sodiumbicarbonate was added to the reaction solution, followed by extractionwith ethyl acetate. The ethyl acetate layers were combined, washed withwater and saturated saline in this order, and dried over anhydroussodium sulfate. The solvent was distilled off, and the obtained residuewas purified by silica gel column chromatography (hexane-ethyl acetate:33:67→15:85) to obtain 294.8 mg (yield: 70%) of compound 6C′ as a paleyellow oil.

1H-NMR (CDCl3) δ: 1.43 (3H, t, J=7.1 Hz), 3.73-3.75 (2H, m), 3.81 (3H,s), 3.82-3.85 (2H, m), 4.21 (2H, d, J=2.2 Hz), 4.42 (2H, q, J=7.1 Hz),5.14 (1H, t, J=2.3 Hz), 5.32 (2H, s), 7.34-7.37 (3H, m), 7.44-7.46 (2H,m), 8.14 (1H, s).

Example 8

Step 1

Aminoacetaldehyde dimethyl acetal (7.80 mmol) was added to an ethanol (5ml) solution of compound 8A (900 mg, 2.60 mmol), and the mixture wasstirred at room temperature for 22 hours. Ethyl acetate (5 ml) and water(5 ml) were added to the reaction solution, followed by extraction withethyl acetate (5 ml). The organic layer was washed with water (10 ml).Then, the solvent was distilled off, and the obtained residue waspurified by silica gel column chromatography (n-hexane-ethyl acetate:2:1) to obtain 0.37 g (yield: 33%) of compound 6C as a colorless oil.

¹H-NMR (CDCl₃) δ: 7.90 (1H, s), 7.45-7.43 (5H, m), 5.30 (2H, s), 4.51(1H, t, J=5.1 Hz), 4.40 (2H, q, J=7.1 Hz), 4.30 (2H, q, J=7.1 Hz), 3.91(2H, d, J=5.1 Hz), 3.46 (6H, s), 1.40 (3H, t, J=7.1 Hz), 1.26 (3H, t,J=7.1 Hz).

Step 2

62% H₂SO₄ (316 mg, 2.0 mmol) was added to a formic acid (4 ml) solutionof compound 6C (433.5 mg, 1.0 mmol), and the mixture was stirred at roomtemperature for 3 hours. Methylene chloride was added to the reactionsolution, and the organic layer was washed with a 0.5 N aqueous sodiumhydroxide solution (12 ml). The aqueous layer was subjected toextraction with methylene chloride. The methylene chloride layers werecombined, washed with saturated saline, and then dried over anhydroussodium sulfate. The solvent was distilled off to obtain 207.6 mg (yield:51%) of compound 8C as a yellow foam.

1H-NMR (CDCl3) δ: 1.23 (3H, t, J=7.1 Hz), 1.42 (3H, t, J=7.1 Hz), 4.25(2H, q, J=7.2 Hz), 4.42 (2H, q, J=7.1 Hz), 4.79 (2H, s), 5.34 (2H, s),7.31-7.53 (5H, m), 8.05 (1H, s), 9.67 (1H, s).

Step 3

Methanol (0.061 ml, 1.5 mmol), (R)-3-amino-butan-1-ol (53.5 mg, 0.60mmol), and acetic acid (0.029 ml, 0.50 mmol) were added to a toluene (2ml) solution of compound 8C (202.6 mg, 0.50 mmol), and the mixture washeated to reflux for 3 hours. The reaction solution was cooled to roomtemperature. Then, methylene chloride was added thereto, and the organiclayer was washed with a saturated aqueous solution of sodiumbicarbonate. The aqueous layer was subjected to extraction withmethylene chloride. The methylene chloride layers were combined, washedwith saturated saline, and then dried over anhydrous sodium sulfate. Thesolvent was distilled off, and the obtained residue was purified bysilica gel column chromatography (chloroform-methanol: 100:0→91:9) toobtain 161.6 mg (yield: 78%) of compound 8D as a yellow foam.

1H-NMR (CDCl3) δ: 1.34 (3H, d, J=7.1 Hz), 1.41 (3H, t, J=7.1 Hz),1.49-1.54 (1H, m), 2.14-2.20 (1H, m), 3.96-3.97 (2H, m), 4.03 (3H, dd,J=13.3, 5.9 Hz), 4.17 (3H, dd, J=13.3, 3.7 Hz), 4.41 (3H, q, J=7.1 Hz),5.01 (1H, t, J=5.6 Hz), 5.17 (1H, dd, J=5.9, 3.9 Hz), 5.33 (2H, d,J=10.1 Hz), 5.39 (2H, d, J=9.9 Hz), 7.33-7.36 (3H, m), 7.68-7.70 (2H,m), 8.05 (1H, s).

Step 4

Compound 8D (50 mg, 0.12 mmol) was dissolved in tetrahydrofuran-methanol(0.5 ml and 0.5 ml, respectively). To this solution, a 1 N aqueoussodium hydroxide solution (0.36 ml, 0.36 mmol) was added, and themixture was stirred at room temperature for 2 hours. The reactionsolution was pH-adjusted to 2.5 by the addition of 1 N hydrochloric acidand subjected to extraction with chloroform. The chloroform layers werecombined, washed with saturated saline, and then dried over anhydroussodium sulfate. The solvent was distilled off to obtain 46.2 mg (yield:99%) of compound 8E as a pale yellow foam.

1H-NMR (CDCl3) δ: 1.38 (3H, d, J=7.1 Hz), 1.53-1.56 (1H, m), 2.16-2.18(1H, m), 3.98-3.99 (2H, m), 4.17 (1H, dd, J=13.3, 5.9 Hz), 4.29 (1H, dd,J=13.4, 3.5 Hz), 5.02 (1H, t, J=6.6 Hz), 5.21 (1H, dd, J=5.5, 3.9 Hz),5.40 (1H, d, J=10.2 Hz), 5.45 (1H, d, J=10.1 Hz), 7.34-7.39 (3H, m),7.60-7.62 (2H, m), 8.33 (1H, s), 15.02 (1H, s).

Step 5

Compound 8E (50 mg, 0.13 mmol) and 2,4-difluorobenzylamine (20.5 mg,0.14 mmol) were dissolved in N,N-dimethylformamide (1 ml). To thesolution, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (HATU) (64 mg, 0.17 mmol) and N-methylmorpholine(0.037 ml, 0.34 mmol) were added, and the mixture was stirred at roomtemperature for 16 hours. HATU (64 mg, 0.17 mmol) and N-methylmorpholine(0.037 ml, 0.34 mmol) were further added thereto, and the mixture wasstirred at room temperature for additional 16 hours. Water was added tothe reaction solution, followed by extraction with ethyl acetate. Theethyl acetate layers were combined, washed with saturated saline, andthen dried over anhydrous sodium sulfate. The solvent was distilled off,and the obtained residue was purified by silica gel columnchromatography (chloroform-methanol: 100:0→95:5) to obtain 48.4 mg(yield: 73%) of compound 8F as a yellow oil.

1H-NMR (CDCl3) δ: 1.36 (4H, d, J=7.1 Hz), 1.50-1.55 (1H, m), 2.16-2.18(1H, m), 3.98-3.99 (2H, m), 4.11 (1H, dd, J=13.4, 6.0 Hz), 4.24 (1H, dd,J=13.5, 3.9 Hz), 4.66 (2H, d, J=5.9 Hz), 5.01-5.04 (1H, m), 5.19 (1H,dd, J=6.0, 3.9 Hz), 5.29 (1H, d, J=10.2 Hz), 5.33 (1H, d, J=9.9 Hz),6.79-6.87 (2H, m), 7.31-7.43 (4H, m), 7.63-7.65 (2H, m), 8.36 (1H, s),10.42 (1H, s).

Example 9

Step 1

In a two-neck flask, compound 9C (291.3 mg, 10 mmol) was dissolved inDMI (1.4 mL) in a nitrogen atmosphere. To the solution, dimethyl oxalate(354.3 mg, 3.0 mmol) and sodium methoxide (28% solution in methanol 0.3mL, 1.5 mmol) was added, and the mixture was stirred at room temperaturefor 2 hours. 2-(aminomethyl)-1,3-dioxane (154.7 mg, 1.5 mmol) and aceticacid (0.29 mL, 5.0 mmol) were added thereto, and the mixture was stirredat room temperature for 5 hours. Ethyl acetate (50 mL) was added to thereaction solution, and the organic layer was washed with water (20 mL),a 10% aqueous ammonium chloride solution (20 mL), water (20 mL), andsaturated saline (20 mL) in this order and dried over anhydrousmagnesium sulfate. The solvent was distilled off, and the obtainedresidue was purified by silica gel column chromatography (n-hexane-ethylacetate: 1:1→1:3, v/v) to obtain 99.0 mg (yield: 25%) of compound 9C′ aswhite crystals.

¹H-NMR (CDCl₃) δ: 8.14 (1H, s), 7.44-7.42 (5H, m), 5.29 (2H, s), 5.12(1H, s), 4.19 (2H, s), 3.93 (3H, s), 3.83-3.70 (2H, m), 3.83 (2H, s).

Example 10

Step 1

Compound 10A (944 mg, 2.33 mmol) was mixed with 2,4-difluorobenzyl amine(401 mg, 2.80 mmol). To the mixture, methanol (2 mL) was added, and themixture was stirred at 60° C. for 1 hour and then at 95° C. for 1.5hours. 2,4-difluorobenzyl amine (401 mg, 2.80 mmol) was further addedthereto, and the mixture was stirred at 95° C. for additional 3 hours. A10% aqueous citric acid solution was added to the reaction solution,followed by extraction with ethyl acetate. The organic layer was washedwith water and saturated saline and dried over anhydrous magnesiumsulfate. The solvent was distilled off, and the obtained residue wasthen purified by silica gel column chromatography to obtain 310 mg(yield: 25%) of compound 10B.

¹H-NMR (CDCl₃) δ: 3.41 (6H, s), 3.82 (3H, s), 4.04 (2H, d, J=4.9 Hz),4.49 (1H, t, J=4.9 Hz), 4.67 (2H, d, J=5.9 Hz), 5.28 (2H, s), 6.79-6.89(2H, m), 7.29-7.46 (5H, m), 8.44 (1H, s), 10.45 (1H, t, J=5.5 Hz).

The acetal moiety of the compound 10B obtained in Example 10 isconverted to an aldehyde group in the same way as in Step 4 of Example3. The resulting compound is reacted with (R)-3-amino-butan-1-ol or(S)-2-amino-propan-1-ol. The benzyl group, which is an alcoholprotective group, can be subjected to deprotection reaction (using, forexample, Pd—C/H₂ gas) to induce the compound (Y1) or (Y2) of interest.

Example 11

Step 1

A dichloromethane (90 mL) solution of compound 11A (12.8 g, 89.4 mmol)and pyridine (8.50 g, 107 mmol) was cooled to 1-3° C., and adichloromethane (90 mL) solution of benzyloxy acetyl chloride (19.8 g,107 mmol) was added dropwise thereto over 50 minutes with the sametemperature kept. The reaction solution was stirred at the sametemperature for 30 minutes and then gradually heated to 15° C. over 60minutes, and ice water was added thereto. The dichloromethane layer wasseparated, while the aqueous layer was subjected to extraction once withdichloromethane. The combined extracts were washed with water threetimes, and washed with saturated saline, and then dried. The solvent wasdistilled off, and the obtained oil was subjected to silica gel columnchromatography for purification. Elution was performed first withn-hexane and then with n-hexane-ethyl acetate (1:1, v/v). The fractionof interest was concentrated to obtain 22.2 g of compound 11B as an oil.

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.2 Hz), 2.90 (3H, brs), 3.24 (3H,brs), 4.15 (2H, q, J=7.2 Hz), 4.45 (2H, s), 4.58 (2H, s), 7.25-7.38 (5H,m), 7.72 (1H, s).

The compound 11B obtained in Example 11 can be used in the next reactionin the same way as in Example 6.

Example 12

Step 1

Aminoacetaldehyde dimethyl acetal (0.72 g, 6.9 mmol) was added dropwiseto a methanol (20 mL) slurry solution of compound 12A (2.0 g, 6.3 mmol)at room temperature, and the mixture was then stirred for 6 hours underheating to reflux. After the completion of reaction, the solvent wasdistilled off under reduced pressure, and the obtained residue waspurified by silica gel chromatography (n-hexane:ethyl acetate=3:17(v/v)) to obtain 2.26 g (yield: 88%) of compound 12B as a colorless oil.

¹H-NMR (CDCl₃) δ: 3.38 (6H, s), 3.81 (3H, s), 3.91 (2H, d, J=4.7 Hz),3.93 (3H, s), 4.47 (1H, t, J=4.7 Hz), 5.29 (2H, s), 7.29-7.37 (3H, m),7.42-7.44 (2H, m), 8.15 (1H, s).

The compound 12B was dried under conditions of concentration underreduced pressure and left standing at 5° C. for approximately 2 months.In this case, this compound was still in an oil form and was notcrystallized. As a result of various studies, however, the compound wassuccessfully crystallized by repeating the addition of ethyl acetate andconcentration and isolated as white crystals.

Step 2

A 62% aqueous sulfuric acid solution (307 mg, 1.9 mmol) was addeddropwise to a formic acid (3.7 mL) solution of compound 12B (525 mg, 1.3mmol) at room temperature, and the mixture was stirred at the sametemperature for 3 hours. After the completion of reaction, the solutionwas cooled to 5° C. and neutralized by the addition of a saturatedaqueous solution of sodium bicarbonate (24.5 g), followed by extractionwith dichloromethane (5 mL×4). The solvent was distilled off underreduced pressure. Then, toluene (5.2 mL) was added to the obtainedresidue, and methanol (125 mg, 3.9 mmol), (R)-3-amino-butan-1-ol (127mg, 1.4 mmol), and acetic acid (78 mg, 1.4 mmol) were further addeddropwise thereto in this order at room temperature. The mixture washeated to 90° C., stirred for 3 hours, and then allowed to cool to roomtemperature. Then, water (2 mL) was added thereto, followed byextraction with ethyl acetate (10 mL×2). The solvent was distilled offunder reduced pressure, and the obtained residue was purified by silicagel chromatography (chloroform:methanol=97:3 (v/v)) to obtain 418 mg(yield: 81%) of compound 12C as a white foam.

¹H-NMR (CDCl₃) δ: 1.33 (3H, d, J=7.1 Hz), 1.50 (2H, dd, J=13.9, 2.3 Hz),2.11-2.20 (1H, m), 3.93 (3H, s), 3.94 (1H, d, J=2.5 Hz), 3.96 (1H, brs), 4.02 (1H, dd, J=13.4, 5.8 Hz), 4.15 (1H, dd, J=13.4, 3.8 Hz),5.04-4.96 (1H, m), 5.16 (1H, dd, J=6.1, 4.1 Hz), 5.35 (2H, dd, J=22.8,10.1 Hz), 7.28-7.36 (3H, m), 7.67 (2H, d, J=7.1 Hz), 8.07 (1H, s).

Step 3

2,4-difluorobenzylamine (75 mg, 0.52 mmol) and acetic acid (31 mg, 0.52mmol) were added dropwise to a toluene (3.4 mL) slurry solution ofcompound 12C (171 mg, 0.43 mmol) at room temperature, and the mixturewas then heated to 100° C. and stirred for 7 hours. After the completionof reaction, the solvent was distilled off under reduced pressure, andthe obtained residue was then purified by silica gel chromatography(chloroform:methanol=97:3 (v/v)) to obtain 150 mg (yield: 69%) ofcompound 12D as yellow crystals.

Example 13

Step 1

2,4-difluorobenzylamine (209 mg, 1.4 mmol) and acetic acid (88 mg, 1.4mmol) were added to a toluene (5.4 mL) suspension of compound 12B (539mg, 1.3 mmol) at room temperature, and the mixture was then heated to90° C. and stirred for 7 hours. After the completion of reaction, thesolvent was distilled off under reduced pressure, and the obtainedresidue was purified by silica gel chromatography (n-hexane:ethylacetate=3:7 (v/v)) to obtain 666 mg (yield: 97%) of compound 13C as apale yellow oil.

¹H-NMR (CDCl₃) δ: 3.37 (6H, s), 3.79 (3H, s), 4.01 (2H, d, J=5.0 Hz),4.47 (1H, t, J=5.0 Hz), 4.65 (2H, d, J=6.0 Hz), 5.26 (2H, s), 6.78-6.86(2H, m), 7.30-7.42 (6H, m), 8.42 (1H, s), 10.41 (1H, t, J=6.0 Hz).

Step 2

A 62% aqueous sulfuric acid solution (306 mg, 1.9 mmol) was added to atoluene (2.7 mL)-formic acid (6.7 mL) solution of compound 13C (666 mg,1.3 mmol) at room temperature, and the mixture was stirred at the sametemperature for 3 hours. After the completion of reaction, the solutionwas cooled to 5° C. and neutralized by the addition of a saturatedaqueous solution of sodium bicarbonate (37.0 g), followed by extractionwith ethyl acetate (10 mL×2). The solvent was distilled off underreduced pressure. Then, toluene (6.7 mL) was added to the obtainedresidue, and methanol (124 mg, 3.9 mmol), (R)-3-amino-butan-1-ol (138mg, 1.6 mmol), and acetic acid (85 mg, 1.4 mmol) were further addeddropwise thereto in this order at room temperature. The mixture washeated to 90° C., stirred for 2 hours, and then allowed to cool to roomtemperature. Then, water (7 mL) was added thereto, followed byextraction with ethyl acetate (10 mL×2). The solvent was distilled offunder reduced pressure, and toluene was added to the residue. Then, thesolvent was distilled off under reduced pressure to bring the contentsto approximately 4.0 g. The residue was concentrated and crystallized.The obtained yellow slurry solution was filtered to obtain 429 mg(yield: 65%) of compound 12D as pale yellow crystals.

Example 14

Step 1

Water (2.5 mL) and aminoacetaldehyde dimethyl acetal (756 μL, 7.0 mmol)were added to compound 14A (1.0 g, 7.1 mmol) at room temperature. Themixture was stirred at 65° C. for 1.5 hours and then stirred at 100° C.for 3.5 hours. After concentration to dryness, crystals were depositedby the addition of water (5 mL). 2-propanol (10 mL) was added thereto,followed by filtration. The crystals were washed with 2-propanol (5 mL)and through-flow-dried to obtain 0.98 g (yield: 76%) of crystals ofcompound 14B.

¹H-NMR (CDCl₃) δ: 4.56 (2H, d, J=4.9 Hz), 5.38 (1H, t, J=4.9 Hz), 7.16(1H, dd, J=7.3 Hz, 2.9 Hz), 7.26 (1H, d, J=2.9 Hz), 8.31 (1H, d, J=7.3Hz).

Step 2

(R)-3-amino-butan-1-ol (75.1 mg, 0.82 mmol) was diluted with 2-propanol(1 mL), and compound 14B (100.6 mg, 0.56 mmol) was added thereto. To themixture, acetic acid (50 μL) was added, and the mixture was stirred at80° C. for 16 hours. The solvent was distilled off, and the obtainedresidue was purified by reverse-phase column chromatography(water-acetonitrile: 95:5→70:30 (v/v)) to obtain 42.0 mg (yield: 32%) ofcompound 14C as an oil.

¹H-NMR (CDCl₃) δ: 1.31 (3H, d, J=7.0 Hz), 1.49 (1H, m), 1.96 (1H, m),3.87 (1H, ddd, J=11.6 Hz, 5.1 Hz, 2.3 Hz), 4.01 (1H, m), 4.12 (1H, dd,J=13.6 Hz, 4.9 Hz), 4.33 (1H, dd, J=13.6 Hz, 4.0 Hz), 4.79 (1H, m), 5.40(1H, dd, J=4.9 Hz, 4.0 Hz), 6.23 (1H, d, J=7.4 Hz, 2.9 Hz), 6.77 (1H, d,J=2.9 Hz), 7.72 (1H, d, J=7.4 Hz).

Step 3

An acetonitrile (1.5 mL) solution of NBS (191.4 mg, 1.08 mmol) was addeddropwise to an acetonitrile (1.5 mL) solution of compound 14C (100.0 mg,0.43 mmol) at room temperature, and the mixture was stirred at roomtemperature for 21 hours (including 30 min at 40° C.). Then, NBS (50.1mg, 0.28 mmol) was further added thereto. After stirring at roomtemperature for 2 hours, the solvent was distilled off. The obtainedresidue was purified by reverse-phase column chromatography(water-acetonitrile: 95:5→40:60 (v/v)) to obtain 30.2 mg (yield: 18%) ofcompound 14D as crystals.

¹H-NMR (CDCl₃) δ: 1.27 (3H, d, J=7.0 Hz), 1.53 (1H, m), 1.96 (1H, m),3.87 (1H, m), 3.95 (1H, m), 4.22 (1H, dd, J=13.5 Hz, 6.2 Hz), 4.45 (1H,dd, J=13.5 Hz, 3.8 Hz), 4.74 (1H, m), 5.37 (1H, dd, J=6.2 Hz, 3.8 Hz),8.50 (1H, s).

Step 4

A 1 mol/L solution of sodium benzyloxide in benzyl alcohol (100 μL, 0.1mmol) was added to a benzyl alcohol (0.5 mL) solution of compound 14D(5.11 mg, 0.013 mmol) at room temperature, and the mixture was stirredat 90° C. for 50 minutes. The obtained reaction solution was purified byreverse-phase column chromatography (water-acetonitrile: 95:5→40:60(v/v)) to obtain 2.98 mg (yield: 55%) of compound 14E as crystals.

¹H-NMR (CDCl₃) δ: 1.27 (3H, d, J=7.0 Hz), 1.59 (1H, m), 1.93 (1H, m),3.84 (1H, m), 3.96 (1H, m), 4.18 (1H, dd, J=13.5 Hz, 5.5 Hz), 4.39 (1H,dd, J=13.5 Hz, 4.0 Hz), 4.77 (1H, m), 5.04 (2H, s), 5.32 (1H, dd, J=5.5Hz, 3.5 Hz), 7.31 (1H, m), 7.39 (2H, m), 7.56 (2H, m), 8.38 (1H, s).

Example 15A: Obtainment of Crystals 15A of Anhydride by Crystallizationof Compound 12C

An ethyl acetate (3 mL) solution of hydroquinone (168 mg, 1.52 mmol) wasadded dropwise to an ethyl acetate (4 mL) solution of compound 12C (1.01g, 2.53 mmol) at room temperature. After stirring at the sametemperature for 1 hour, the obtained slurry solution was filtered toobtain 0.95 g (yield: 81%) of compound 15A as pale yellow crystals. Thecompound 15A was confirmed to be hydroquinone hemisolvate crystals ofcompound 12C.

¹H-NMR (CDCl₃) δ: 1.32 (3H, d, J=7.1 Hz), 1.50 (1H, dd, J=14.2, 2.0 Hz),2.16 (1H, ddd, J=21.8, 8.1, 5.8 Hz), 3.93 (3H, s), 3.94-3.97 (2H, m),4.02 (1H, dd, J=13.2, 6.1 Hz), 4.15 (1H, dd, J=13.2, 3.5 Hz), 4.58 (1H,br s), 5.00 (1H, td, J=6.7, 2.2 Hz), 5.16 (1H, dd, J=6.1, 3.5 Hz), 5.34(2H, dd, J=22.8, 10.1 Hz), 6.72 (1H, s), 7.32 (3H, dt, J=18.9, 5.4 Hz),7.66 (2H, d, J=7.1 Hz), 8.07 (1H, s).

Example 15B: Obtainment of Crystals 15B of Hydrate by Crystallization ofCompound 15A

Water (500 μL) was added to compound 15A (50 mg) at room temperature,and the mixture was stirred at the same temperature for 1 hour and thenstirred at 70° C. for 2 hours. Then, the obtained slurry solution wasfiltered to obtain compound 15B as pale yellow crystals. The compound15B was confirmed to be hemihydrate and hydroquinone hemisolvatecrystals of compound 12C.

Example 16

Measurement of Powder X-Ray Diffraction Pattern

The powder X-ray diffractometry of the crystals obtained in each Examplewas performed under the following measurement conditions according tothe powder X-ray diffractometry described in the general test methods ofthe Japanese Pharmacopoeia.

(Apparatus)

D-8 Discover Manufactured by Bruker Corp.

(Operation Procedure)

Each sample was assayed under the following conditions:

Measurement method: Reflection method

Type of light source: Cu tube

Wavelength used: CuKα rays

Tube current: 40 mA

Tube voltage: 40 Kv

Sample plate: glass

X-ray incident angle: 3° and 12°

Methods for producing diastereomers A-5 and B-5 of compound 3H will beshown below in Reference Examples.

Reference Example 1

Step 1

Acetic acid (180 mg, 3.00 mmol) was added to a toluene (90 ml) solutionof compound A-1 (4.39 g, 9.33 mmol) and (R)-3-aminobutan-1-ol (998 mg,11.2 mmol), and the mixture was stirred at 50° C. for 90 minutes. Thereaction solution was allowed to cool to room temperature and thenpoured to a saturated aqueous solution of sodium bicarbonate. Theorganic layer was separated, while the aqueous layer was subjected toextraction three times with ethyl acetate. The combined extracts werewashed with saturated saline and then dried over sodium sulfate. Thesolvent was distilled off to obtain 4.29 g of crude product A-2.

Step 2

The crude product A-2 obtained in the preceding step was dissolved inethanol (40 ml). To the solution, a 2 N aqueous sodium hydroxidesolution (20 ml) was added at room temperature, and the mixture wasstirred at the same temperature for 2 hours. The reaction solution wasneutralized to pH 7 using a 2 N aqueous hydrochloric acid solution. Thesolvent was directly distilled off. The obtained crude product A-3 wassubjected to azeotropy with toluene (100 ml) and used in the next stepwithout being purified.

Step 3

HOBt (1.65 g, 12.2 mmol) and WSC HCl (2.34 g, 12.2 mmol) were added atroom temperature to a DMF (100 ml) solution of the crude product A-3obtained in the preceding step, and the mixture was stirred at the sametemperature for 15 hours. Water was added to the reaction solution,followed by extraction three times with ethyl acetate. The combinedextracts were washed with water three times and then dried over sodiumsulfate. The solvent was distilled off, and the obtained oil wassubjected to silica gel column chromatography for purification. Elutionwas performed first with n-hexane-ethyl acetate (3:7, v/v) and then withonly ethyl acetate. The fraction of interest was concentrated, and theobtained oil was then dissolved in ethyl acetate. The solution wascrystallized with diisopropyl ether as a poor solvent. The obtainedcrystals were collected by filtration and dissolved again in ethylacetate. The solution was recrystallized to obtain 1.84 g of compoundA-4.

¹HNMR (CDCl₃) δ: 1.49 (3H, d, J=6.6 Hz), 1.88-1.96 (1H, m), 2.13-2.26(1H, m), 3.90-4.17 (4H, m), 4.42-4.47 (1H, m), 4.63 (2H, d, J=6.0 Hz),5.12-5.17 (1H, m), 5.17 (1H, d, J=9.9 Hz), 5.33 (1H, d, J=9.9 Hz),6.77-6.87 (2H, m), 7.27-7.42 (4H, m), 7.59-7.62 (2H, m), 8.35 (1H, s),10.41 (1H, t, J=5.7 Hz).

Step 4

The compound A-4 was subjected to the hydroxy deprotection reactiondescribed in Step F to obtain compound A-5.

¹HNMR (DMSO-d₆) δ: 1.41 (3H, d, J=6.3 Hz), 1.85-1.92 (1H, m), 1.50-1.75(1H, m), 4.02-4.09 (3H, m), 4.28-4.34 (1H, m), 4.53 (2H, d, J=5.7 Hz),4.64 (1H, dd, J=3.9 Hz, 12.6 Hz), 5.45 (1H, dd, J=3.6 Hz, 9.3 Hz), 7.06(1H, ddd, J=2.7 Hz, 8.4 Hz, 8.4 Hz), 7.20-7.28 (1H, m), 7.35-7.42 (1H,m), 8.43 (1H, s), 10.37 (1H, t, J=6.0 Hz), 12.37 (1H, brs).

Reference Example 2

Compound A-1 was reacted with (S)-3-aminobutan-1-ol in Step 1. CompoundB-5 was obtained in the same way as in Reference Example 1.

¹HNMR (DMSO-d₆) δ: 1.41 (3H, d, J=6.3 Hz), 1.85-1.92 (1H, m), 1.50-1.75(1H, m), 4.02-4.09 (3H, m), 4.28-4.34 (1H, m), 4.53 (2H, d, J=5.7 Hz),4.64 (1H, dd, J=3.9 Hz, 12.6 Hz), 5.45 (1H, dd, J=3.6 Hz, 9.3 Hz), 7.06(1H, ddd, J=2.7 Hz, 8.4 Hz, 8.4 Hz), 7.20-7.28 (1H, m), 7.35-7.42 (1H,m), 8.43 (1H, s), 10.37 (1H, t, J=6.0 Hz), 12.37 (1H, brs).

INDUSTRIAL APPLICABILITY

Use of the production method according to the present invention canreduce the number of steps for producing compounds having HIV integraseinhibitory activity from, for example, conventionally required 16 to 11steps to preferably 8 to 6 steps. Thus, the production method of thepresent invention is applicable as an efficient industrial productionmethod and as such, has industrial applicability.

The invention claimed is:
 1. A crystal form of a compound of formula(U2):

which is characterized by an X-ray powder diffraction spectrumcomprising peaks at an angle of refraction 2θ of 7.3°±0.2°, 14.4°±0.2°,16.1°±0.2°, 18.4°±0.2°, 22.3°±0.2° and 23.1°±0.2°.